Heterocyclic compounds

ABSTRACT

Organic compounds having the structural formulas I, II, and III are provided where the variables have the values described herein and R 1  and R 2  in structure I join together to form a 5 to 7 membered substituted or unsubstituted ring including at least one O, N, or S atom, and Z is an O, S, NH or NR group in structures I and II.  
                 
 
     Pharmaceutical formulations include the organic compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A method of treating a patient includes administering a pharmaceutical formulation according to the invention to a patient in need thereof.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional ApplicationNo. 60/231,829 filed on Sep. 1, 2000, the entire disclosure of which isincorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention pertains generally to treating diseasescharacterized by angiogenesis including cancer. More specifically, theinvention described herein pertains to treating diseases characterizedby activity of vascular endothelial growth factor receptor tyrosinekinases. The present invention provides small molecule inhibitors ofvascular endothelial growth factor receptor tyrosine kinase,pharmaceutical formulations containing such inhibitors, methods oftreating patients with such pharmaceutical formulations, and to methodsof preparing such pharmaceutical formulations and inhibitors.

BACKGROUND OF THE INVENTION

[0003] Capillaries reach into almost all tissues of the human body andsupply tissues with oxygen and nutrients as well as removing wasteproducts. Under typical conditions, the endothelial cells lining thecapillaries do not divide, and capillaries, therefore, do not normallyincrease in number or size in a human adult. Under certain normalconditions, however, such as when a tissue is damaged, or during certainparts of the menstrual cycle, the capillaries begin to proliferaterapidly. This process of forming new capillaries from pre-existing bloodvessels is known as angiogenesis or neovascularization. See Folkman, J.Scientific American 275, 150-154 (1996). Angiogenesis during woundhealing is an example of pathophysiological neovascularization duringadult life. During wound healing, the additional capillaries provide asupply of oxygen and nutrients, promote granulation tissue, and aid inwaste removal. After termination of the healing process, the capillariesnormally regress. Lymboussaki, A. “Vascular Endothelial Growth Factorsand their Receptors in Embryos, Adults, and in Tumors” AcademicDissertation, University of Helsinki, Molecular/Cancer BiologyLaboratory and Department of Pathology, Haartman Institute, (1999).

[0004] Angiogenesis also plays an important role in the growth of cancercells. It is known that once a nest of cancer cells reaches a certainsize, roughly 1 to 2 mm in diameter, the cancer cells must develop ablood supply in order for the tumor to grow larger as diffusion will notbe sufficient to supply the cancer cells with enough oxygen andnutrients. Thus, inhibition of angiogenesis is expected to retard orhalt the growth of cancer cells.

[0005] Receptor tyrosine kinases (RTKs) are transmembrane polypeptidesthat regulate developmental cell growth and differentiation andremodeling and regeneration of adult tissues. Mustonen, T. et al., J.Cell Biology 129, 895-898 (1995); van der Geer, P. et al. Ann Rev. CellBiol. 10, 251-337 (1994). Polypeptide ligands known as growth factors,or cytokines, are known to activate RTKs. Signaling of RTKs involvesligand binding and a shift in conformation in the external domain of thereceptor resulting in its dimerization. Lymboussaki, A. “VascularEndothelial Growth Factors and their Receptors in Embryos, Adults, andin Tumors” Academic Dissertation, University of Helsinki,Molecular/Cancer Biology Laboratory and Department of Pathology,Haartman Institute, (1999); Ullrich, A. et al., Cell 61, 203-212 (1990).Binding of the ligand to the RTK results in receptortrans-phosphorylation at specific tyrosine residues and subsequentactivation of the catalytic domains for the phosphorylation ofcytoplasmic substrates. Id.

[0006] Two subfamilies of RTKs are specific to the vascular endothelium.These include the vascular endothelial growth factor (VEGF) subfamilyand the Tie receptor subfamily. Class III RTKs include VEGFR-1, VEGFR-2,and VEGFR-3. Shibuya, M. et al., Oncogene 5, 519-525 (1990); Terman, B.et al., Oncogene 6, 1677-1683 (1991); Aprelikova, O. et al., Cancer Res.52, 746-748 (1992).

[0007] Members of the VEGF subfamily have been described as being ableto induce vascular permeability and endothelial cell proliferation andfurther identified as a major inducer of angiogenesis andvasculogenesis. Ferrara, N. et al., Endocrinol. Rev. 18, 4-25 (1997).VEGF is known to specifically bind to RTKs including VEGFR-1 andVEGFR-2. DeVries, C. et al., Science 255, 989-991 (1992); Quinn, T. etal., Proc. Natl. Acad. Sci. 90, 7533-7537 (1993). VEGF stimulates themigration and proliferation of endothelial cells and inducesangiogenesis both in vitro and in vivo. Connolly, D. et al., J. Biol.Chem. 264, 20017-20024 (1989); Connolly, D. et al., J. Clin. Invest. 84,1470-1478 (1989); Ferrara, N. et al., Endocrino. Rew. 18, 4-25 (1997);Leung, D. et al., Science 246, 1306-1309 (1989); Plouet, J. et al., EMBOJ 8, 3801-3806 (1989).

[0008] Because angiogenesis is known to be critical to the growth ofcancer and to be controlled by VEGF and VEGF-RTK, substantial effortshave been undertaken to develop therapeutics that are antagonists ofVEGF-RTK to thereby inhibit or retard angiogenesis, and hopefullyinterfere or stop tumor proliferation.

[0009] A wide variety of chemical compounds and compositions have beenreported as having activity against one of more the VEGF-RTKs. Examplesinclude quinoline derivatives such as described in WO 98/13350,aminonicotinamide derivatives (see, e.g., WO 01/55114), antisensecompounds (see, e.g., WO 01/52904), peptidomimetics (see, e.g., WO01/52875), quinazoline derivatives (see, e.g., U.S. Pat. No. 6,258,951)monoclonal antibodies (see, e.g., EP 1 086 705 A1), various5,10,15,20-tetraaryl-porphyrins and 5,10,15-triaryl-corroles (see, e.g.,WO 00/27379), heterocyclic alkanesulfonic and alkane carboxylic acidderivatives (see, e.g., DE19841985), oxindolylquinazoline derivatives(see, e.g., WO 99/10349), 1,4-diazaanthracine derivatives (see, e.g.,U.S. Pat. No. 5,763,441), and cinnoline derivatives (see, e.g., WO97/34876), and various indazole compounds (see e.g., WO 01/02369 and WO01/02369).

[0010] Various indolyl-substituted compounds have recently beendisclosed in WO 01/29025, and various benzimidazolyl compounds haverecently been disclosed in WO 01/28993. These compounds are reportedlycapable of inhibiting, modulating, and/or regulating signal transductionof both receptor-type and non-receptor tyrosine kinases. Some of thedisclosed compounds contain a quinolone fragment bonded to the indolylor benzimidazolyl group.

[0011] The synthesis of 4-hydroxy quinolone and 4-hydroxy quinolinederivatives is disclosed in a number of references. For example,Ukrainets et al. have disclosed the synthesis of3-(Benzimidazol-2-yl)-4-hydroxy-2-oxo-1,2-dihydroquinoline. Ukrainets,I. et al., Tet. Lett. 42, 7747-7748 (1995); Ukrainets, I. et al.,Khimiya Geterotsiklicheskikh Soedinii, 2, 239-241(1992). Ukrainets hasalso disclosed the synthesis, anticonvulsive and antithyroid activity ofother 4-hydroxy quinolones and thio analogs such as1H-2-oxo-3-(2-benzimidazolyl)-4-hyrdoxyquinoline. Ukrainets, I. et al.,Khimiya Geterotsiklicheskikh Soedinii, 1, 105-108 (1993); Ukrainets, I.et al., Khimiya Geterotsiklicheskikh Soedinii, 8, 1105-1108 (1993);Ukrainets, I. et al., Chem. Heterocyclic Comp. 33, 600-604, (1997).

[0012] The synthesis of various quinoline derivatives is disclosed in WO97/48694. These compounds are disclosed as capable of binding to nuclearhormone receptors and being useful for stimulating osteoblastproliferation and bone growth. The compounds are also disclosed as beinguseful in the treatment or prevention of diseases associated withnuclear hormone receptor families.

[0013] Various quinoline derivatives in which the benzene ring of thequinolone is substituted with a sulfur group are disclosed in WO92/18483. These compounds are disclosed as being useful inpharmaceutical formulations and as medicaments.

[0014] Quinolone and coumarin derivatives have been disclosed as havinguse in a variety of applications unrelated to medicine andpharmaceutical formulations. References that describe the preparation ofquinolone derivatives for use in photopolymerizable compositions or forluminescent properties include: U.S. Pat. No. 5,801,212 issued toOkamoto et al.; JP 8-29973; JP 7-43896; JP 6-9952; JP 63-258903; EP797376; and DE 23 63 459.

[0015] Despite the exploration of a variety of chemistries to provideVEGF-RTK-antagonist therapies, a continuing need exists for compoundsthat inhibit the proliferation of capillaries, inhibit the growth oftumors, and/or inhibit vascular endothelial growth factor receptortyrosine kinase and pharmaceutical formulations that contain suchcompounds. A need also exists for methods for administering suchcompounds and pharmaceutical formulations to patients in need thereof.

SUMMARY OF THE INVENTION

[0016] The present invention provides compounds, pharmaceuticalformulations including the compounds, methods of preparing thepharmaceutical formulations, and methods of treating patients with thepharmaceutical formulations and compounds.

[0017] The present invention provides compounds having the structure I.The invention also provides tautomers of the compounds, pharmaceuticallyacceptable salts of the compounds, and pharmaceutically acceptable saltsof the tautomers. Structure I has the following formula:

[0018] where:

[0019] Y is selected from —OH, —OR⁸ groups, —SH, —SR⁹ groups, —NR¹⁰R¹¹groups, —CN, —C(═O)—R¹² groups, substituted or unsubstituted alkylgroups, substituted or unsubstituted alkenyl groups, substituted orunsubstituted alkynyl groups, substituted or unsubstituted aralkylgroups, substituted or unsubstituted heterocyclylalkyl groups,substituted or unsubstituted alkylaminoalkyl groups, substituted orunsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted or unsubstituted heterocyclylaminoalkyl groups, substitutedand unsubstituted diheterocyclylaminoalkyl groups, substituted andunsubstituted (alkyl)(heterocyclyl)aminoalkyl groups, substituted andunsubstituted (aryl)(heterocyclyl)aminoalkyl groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstituted arylgroups, substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups;

[0020] Z is O, S, or a NR¹³ group;

[0021] R¹ and R² join to form a 5 to 7 membered substituted orunsubstituted ring including at least one O, N, or S atom;

[0022] R³ and R¹³ may be the same or different and are selected from H,—OH, substituted or unsubstituted alkoxy groups, substituted orunsubstituted aryloxy groups, —NH₂, substituted or unsubstitutedalkylamino groups, substituted or unsubstituted arylamino groups,substituted or unsubstituted dialkylamino groups, substituted orunsubstituted diarylamino groups, substituted or unsubstituted(alkyl)(aryl)amino groups, substituted and unsubstitutedheterocyclylamino groups, substituted and unsubstituteddiheterocyclylamino groups, substituted and unsubstituted(alkyl)(heterocyclyl)amino groups, substituted and unsubstituted(aryl)(heterocyclyl)amino groups, substituted and unsubstitutedheterocylyloxy groups, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —C(═O)H, —C(═O)-alkyl groups,or —C(═O)-aryl groups;

[0023] R⁴, R⁵, R⁶, and R⁷ may be the same or different and areindependently selected from H, Cl, Br, F, I, —NO₂, —CN, —OH, —OR¹⁴groups, —NR¹⁵R¹⁶ groups, —C(═O)R¹⁷ groups, —SH, —SR¹⁸ groups, —S(═O)R¹⁹groups, S(═O)₂R²⁰ groups, substituted or unsubstituted amidinyl groups,substituted or unsubstituted guanidinyl groups, substituted orunsubstituted primary, secondary, or tertiary alkyl groups, substitutedor unsubstituted aryl groups, substituted or unsubstituted alkenylgroups, substituted or unsubstituted alkynyl groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstitutedalkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkylgroups, substituted or unsubstituted arylaminoalkyl groups, substitutedor unsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, substituted or unsubstituted aminoalkylgroups, substituted or unsubstituted heterocyclylaminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups;

[0024] R⁸ is selected from substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted heterocyclylalkylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups,—N(alkyl)₂ groups, —N(alkyl)(aryl) groups, —N(aryl)₂ groups,—C(═O)NH(heterocyclyl) groups, —C(═O)N(heterocyclyl)₂ groups,—C(═O)N(alkyl)(heterocyclyl) groups, or —C(═O)N(aryl)(heterocyclyl)groups;

[0025] R⁹ and R¹⁸ may be the same or different and are independentlyselected from substituted or unsubstituted alkyl groups, or substitutedor unsubstituted aryl groups;

[0026] R¹⁰ is selected from H, substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, or substituted orunsubstituted heterocyclyl groups;

[0027] R¹¹ is selected from H, substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, substituted orunsubstituted heterocyclyl groups, —OH, alkoxy groups, aryloxy groups,—NH₂, substituted or unsubstituted heterocyclylalkyl groups, substitutedor unsubstituted aminoalkyl groups, substituted or unsubstitutedalkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkylgroups, substituted or unsubstituted arylaminoalkyl groups, substitutedor unsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylaminogroups, substituted or unsubstituted arylamino groups, substituted orunsubstituted dialkylamino groups, substituted or unsubstituteddiarylamino groups, substituted or unsubstituted (alkyl)(aryl)aminogroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted or unsubstitutedhydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups,substituted or unsubstituted aryloxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups;

[0028] R¹² is selected from H, —OH, alkoxy groups, aryloxy groups, —NH₂,—NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂groups, —N(alkyl)(aryl) groups, substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, —NH(heterocyclyl)groups, —N(heterocyclyl)₂ groups, —N(alkyl)(heterocyclyl) groups, or—N(aryl)(heterocyclyl) groups;

[0029] R¹⁴ is selected from substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted heterocyclylalkylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups,—C(═O)-heterocyclyl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)NH-heterocyclyl groups,—C(═O)N-(heterocyclyl)₂ groups, —C(═O)N(alkyl)(heterocyclyl) groups,—C(═O)N(aryl)(heterocyclyl) groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups,substituted or unsubstituted dialkylaminoalkyl groups, substituted orunsubstituted arylaminoalkyl groups, substituted or unsubstituteddiarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituteddiheterocyclylaminoalkyl groups, substituted or unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedalkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups,substituted or unsubstituted hydroxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups;

[0030] R¹⁵ is selected from H, substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, or substituted orunsubstituted heterocyclyl groups;

[0031] R¹⁶ is selected from H, substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, substituted orunsubstituted heterocyclyl groups, —C(═O)H, —C(═O)-alkyl groups,—C(═O)-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl)groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups,substituted or unsubstituted aminoalkyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substitutedor unsubstituted heterocyclylalkyl groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedhydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups,substituted or unsubstituted aryloxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups; and

[0032] R¹⁷, R¹⁹, and R²⁰ may be the same or different and areindependently selected from H, —NH₂, —NH(alkyl) groups, —NH(aryl)groups, —N(alkyl)₂ groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups,—NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups,—N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, substituted andunsubstituted alkyl groups, substituted and unsubstituted aryl groups,—OH, substituted and unsubstituted alkoxy groups, substituted andunsubstituted heterocyclyl groups, substituted and unsubstituted aryloxygroups, heterocyclyloxy groups, —NHOH, —N(alkyl)OH groups, —N(aryl)OHgroups, —N(alkyl)O-alkyl groups, —N(aryl)O-alkyl groups, —N(alkyl)O-arylgroups, and —N(aryl)O-aryl groups.

[0033] Preferred compounds having the structure I are provided where Yis selected from —OH, —OR⁸ groups, or —NR¹⁰R¹¹ groups, or morepreferably is a —NR¹⁰R¹¹ group.

[0034] Still other preferred compounds having the structure I areprovided in which Z is an NR¹³ group and the rest of the compound isconsistent with any of the above-described compounds.

[0035] In still other preferred compounds of structure I, R⁴ and R⁷ arehydrogen, R⁶ and R⁷ are selected from hydrogen or an alkyl group havingfrom 1 to 4 carbon atoms, and the rest of the compound is consistentwith any of the above-described compounds.

[0036] Still other compounds having the formula of structure I areprovided in which R⁵ or R⁶ is an —OR¹⁴ group and R¹⁴ is an alkyl, aryl,heterocyclyl, or heterocyclylalkyl group and the rest of the molecule isconsistent with any of the above-described compounds.

[0037] In still further preferred compounds having the formula ofstructure I, R⁵ or R⁶ is a —OCH₂(CH₂)_(q)(heterocyclyl) group where q is0, 1, 2, 3, or 4 and the rest of the compound is consistent with any ofthe above-described compounds.

[0038] Other preferred compounds having the structure I are provided inwhich R¹⁷ is selected from substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —NH₂, —NH(alkyl) groups,—N(alkyl)₂ groups, —NH(aryl) groups, —N(aryl)₂ groups, —N(alkyl)(aryl)groups, —NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups,—N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, or N-containingheterocycles, and the N-containing heterocycles are bonded to thecarbonyl carbon of the —C(═O)—R¹⁷ group through either a nitrogen atomor a carbon atom in the rings of the N-containing heterocycles.

[0039] The present invention also provides compounds having thestructure III. The invention also provides tautomers of the compounds,pharmaceutically acceptable salts of the compounds, and pharmaceuticallyacceptable salts of the tautomers. Structure III has the followingformula:

[0040] where:

[0041] W¹, W², W³, and W⁴ are selected from C or N, and at least one ofW¹, W²W³, or W⁴ is N;

[0042] X¹, X², X³, and X⁴ are selected from C or N, and at least one ofX¹, X², X³, or X⁴is N;

[0043] Y is selected from H, —OH, —OR¹⁰ groups, —SH, —SR¹¹ groups,—NR¹²R¹³ groups, —CN, —C(═O)—R¹⁴ groups, substituted or unsubstitutedalkyl groups, substituted or unsubstituted alkenyl groups, substitutedor unsubstituted alkynyl groups, substituted or unsubstituted aralkylgroups, substituted or unsubstituted heterocyclylalkyl groups,substituted or unsubstituted alkylaminoalkyl groups, substituted orunsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted or unsubstituted heterocyclylaminoalkyl groups, substitutedand unsubstituted diheterocyclylaminoalkyl groups, substituted andunsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted andunsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstituted arylgroups, substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups;

[0044] R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ may be the same or differentand are independently selected from H, Cl, Br, F, I, —NO₂, —CN, —OH,—OR¹⁵ groups, —NR¹⁶R¹⁷ groups, —C(═O)R¹⁸ groups, —SH, —SR¹⁹ groups,—S(═O)R²⁰ groups, S(═O)₂R¹⁹ groups, substituted or unsubstitutedamidinyl groups, substituted or unsubstituted guanidinyl groups,substituted or unsubstituted primary, secondary, or tertiary alkylgroups, substituted or unsubstituted aryl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substitutedor unsubstituted heterocyclylalkyl groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkylgroups, substituted and unsubstituted diheterocyclylaminoalkyl groups,substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups,substituted and unsubstituted (aryl)(heterocyclyl)aminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups, and R¹ is absent or H if W¹ is N, R² isabsent or H if W² is N, R³ is absent or H if W³ is N, R⁴ is absent or Hif W⁴ is N, R⁵ is absent or H if X¹ is N, R⁶ is absent or H if X² is N,R⁷ is absent or H if X³ is N, and R⁸ is absent or H if X⁴ is N;

[0045] R⁹ is selected from H, —OH, substituted or unsubstituted alkoxygroups, substituted or unsubstituted aryloxy groups, —NH₂, substitutedor unsubstituted alkylamino groups, substituted or unsubstitutedarylamino groups, substituted or unsubstituted dialkylamino groups,substituted or unsubstituted diarylamino groups, substituted orunsubstituted (alkyl)(aryl)amino groups, substituted or unsubstitutedalkyl groups, substituted or unsubstituted aryl groups, —C(═O)H,—C(═O)-alkyl groups, or —C(═O)-aryl groups;

[0046] R¹⁰ is selected from substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted heterocyclylalkylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups,—N(alkyl)₂ groups, —N(alkyl)(aryl) groups, —N(aryl)₂ groups,—C(═O)NH(heterocyclyl) groups, —C(═O)N(heterocyclyl)₂ groups,—C(═O)N(alkyl)(heterocyclyl) groups, or —C(═O)N(aryl)(heterocyclyl)groups;

[0047] R¹⁰ and R¹⁹ may be the same or different and are independentlyselected from substituted or unsubstituted alkyl groups, or substitutedor unsubstituted aryl groups;

[0048] R¹² is selected from H, substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, or substituted orunsubstituted heterocyclyl groups;

[0049] R¹³ is selected from H, substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, substituted orunsubstituted heterocyclyl groups, —OH, alkoxy groups, aryloxy groups,—NH₂, substituted or unsubstituted heterocyclylalkyl groups, substitutedor unsubstituted aminoalkyl groups, substituted or unsubstitutedalkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkylgroups, substituted or unsubstituted arylaminoalkyl groups, substitutedor unsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylaminogroups, substituted or unsubstituted arylamino groups, substituted orunsubstituted dialkylamino groups, substituted or unsubstituteddiarylamino groups, substituted or unsubstituted (alkyl)(aryl)aminogroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkylgroups, substituted or unsubstituted alkoxyalkyl groups, substituted orunsubstituted aryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups;

[0050] R¹⁴ is selected from H, —OH, alkoxy groups, aryloxy groups, —NH₂,—NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂groups, —N(alkyl)(aryl) groups, substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, —NH(heterocyclyl)groups, —N(heterocyclyl)₂ groups, —N(alkyl)(heterocyclyl) groups, or—N(aryl)(heterocyclyl) groups;

[0051] R¹⁵ is selected from substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted heterocyclylalkylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups,—(C═O)-heterocyclyl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)NH-heterocyclyl groups,—C(═O)N-(heterocyclyl)₂ groups, —C(═O)N(alkyl)(heterocyclyl) groups,—C(═O)N(aryl)(heterocyclyl) groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups,substituted or unsubstituted dialkylaminoalkyl groups, substituted orunsubstituted arylaminoalkyl groups, substituted or unsubstituteddiarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituteddiheterocyclylaminoalkyl groups, substituted or unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedalkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups,substituted or unsubstituted hydroxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups;

[0052] R¹⁶ is selected from H, substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, or substituted orunsubstituted heterocyclyl groups;

[0053] R¹⁷ is selected from H, substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, substituted orunsubstituted heterocyclyl groups, —C(═O)H, —C(═O)-alkyl groups,—C(═O)-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl)groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups,substituted or unsubstituted aminoalkyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,substituted or unsubstituted (aryl)(alkyl)aminoalkyl groups, substitutedor unsubstituted heterocyclylalkyl groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedhydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups,substituted or unsubstituted aryloxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups; and

[0054] R¹⁸, R²⁰, and R²¹ may be the same or different and areindependently selected from H, —NH₂, —NH(alkyl) groups, —NH(aryl)groups, —N(alkyl)₂ groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups,—NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups,—N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups,—OH, substituted or unsubstituted alkoxy groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstituted aryloxygroups, heterocyclyloxy groups, —NHOH, —N(alkyl)OH groups, —N(aryl)OHgroups, —N(alkyl)O-alkyl groups, —N(aryl)O-alkyl groups, —N(alkyl)O-arylgroups, and —N(aryl)O-aryl groups.

[0055] Preferred compounds having structure III are also provided whereone of W¹, W², W³, or W⁴ is N.

[0056] Preferred compounds having structure III are also provided whereone of X¹, X², X³, or X⁴ is N.

[0057] Preferred compounds having structure III are also provided whereY is selected from H, —OH, —OR¹⁰ groups, or —NR¹²R¹³ groups, or morepreferably is a —NR¹²R¹³ group.

[0058] Still other preferred compounds having structure III are providedwhere R⁵ is H, X⁴ is N, R⁶ and R⁷ are selected from H or alkyl groupshaving from one to four carbon atoms, and the rest of the compound isconsistent with any of the above-described compounds.

[0059] Still other compounds of structure III are provided in which R⁶or R⁷ is an —OR¹⁵ group and R¹⁵ is an alkyl, aryl, heterocyclyl, orheterocyclylalkyl group and the rest of the molecule is consistent withany of the above-described compounds.

[0060] In still further preferred compounds of structure III, R⁶ or R⁷is a —OCH₂(CH₂)_(q)(heterocyclyl) group, q is 0, 1, 2, 3, or 4, and therest of the compound is consistent with any of the above-describedcompounds.

[0061] Other preferred compounds having the structure III are providedin which R¹⁸ is selected from substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —NH₂, —NH(alkyl) groups,—N(alkyl)₂ groups, —NH(aryl) groups, —N(aryl)₂ groups, —N(alkyl)(aryl)groups, —NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups,—N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, or N-containingheterocycles, and the N-containing heterocycles are bonded to thecarbonyl carbon of the —C(═O)—R¹⁸ group through either a nitrogen atomor a carbon atom in the rings of the N-containing heterocycles.

[0062] Pharmaceutical formulations according to the present inventionare provided which include any of the compounds described above incombination with a pharmaceutically acceptable carrier.

[0063] A method of treating a patient in need of an inhibitor ofvascular endothelial growth factor receptor tyrosine kinase is providedwhich includes administering an effective amount of the pharmaceuticalformulation according to the present invention to a patient in needthereof.

[0064] Further objects, features and advantages of the invention will beapparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

[0065] The present invention provides novel compounds that act asantagonists of receptor tyrosine kinases, and, more particularly, asinhibitors of bFGF and VEGF-RTK function. The compounds provided hereincan be formulated into pharmaceutical formulations that are useful intreating patients with a need for an inhibitor of VEGF-RTK, especially,in particular embodiments, to provide compositions and methods forreducing capillary proliferation and in the treatment of cancer.

[0066] The following abbreviations and definitions are used throughoutthis application:

[0067] “VEGF” is an abbreviation that stands for vascular endothelialgrowth factor.

[0068] “RTK” is an abbreviation that stands for receptor tyrosinekinase.

[0069] “VEGF-RTK” is an abbreviation that stands for vascularendothelial growth factor receptor tyrosine kinase.

[0070] “Flt-1” is an abbreviation that stands for fms-like tyrosinekinase-1, also known as vascular endothelial growth factor receptor-1 or“VEGFR1”.

[0071] “KDR” is an abbreviation that stands for kinase-insert domaintyrosine kinase, also known as vascular endothelial growth factorreceptor-2 or “VEGFR2”.

[0072] “bFGF” is an abbreviation that stands for basic fibroblast growthfactor.

[0073] “bFGFR” is an abbreviation that stands for basic fibroblastgrowth factor receptor.

[0074] Generally, reference to a certain element such as hydrogen or His meant to include all isotopes of that element. For example, if an Rgroup is defined to include hydrogen or H, it also includes deuteriumand tritium.

[0075] The phrase “unsubstituted alkyl” refers to alkyl groups that donot contain heteroatoms. Thus the phrase includes straight chain alkylgroups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase alsoincludes branched chain isomers of straight chain alkyl groups,including but not limited to, the following which are provided by way ofexample: —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —CH(CH₂CH₃)₂, —C(CH₃)₃,—C(CH₂CH₃)₃, —CH₂CH(CH₃)₂, —CH₂CH(CH₃)(CH₂CH₃), —CH₂CH(CH₂CH₃)₂,—CH₂C(CH₃)₃, —CH₂C(CH₂CH₃)₃, —CH(CH₃)CH(CH₃)(CH₂CH₃), —CH₂CH₂CH(CH₃)₂,—CH₂CH₂CH(CH₃)(CH₂CH₃), —CH₂CH₂CH(CH₂CH₃)₂, —CH₂CH₂C(CH₃)₃,—CH₂CH₂C(CH₂CH₃)₃, —CH(CH₃)CH₂CH(CH₃)₂, —CH(CH₃)CH(CH₃)CH(CH₃)₂,—CH(CH₂CH₃)CH(CH₃)CH(CH₃)(CH₂CH₃), and others. The phrase also includescyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted withstraight and branched chain alkyl groups as defined above. The phrasealso includes polycyclic alkyl groups such as, but not limited to,adamantyl and norbornyl and such rings substituted with straight andbranched chain alkyl groups as defined above. Thus the phraseunsubstituted alkyl groups includes primary alkyl groups, secondaryalkyl groups, and tertiary alkyl groups. Unsubstituted alkyl groups maybe bonded to one or more carbon atom(s), oxygen atom(s), nitrogenatom(s), and/or sulfur atom(s) in the parent compound. Preferredunsubstituted alkyl groups include straight and branched chain alkylgroups and cyclic alkyl groups having 1 to 20 carbon atoms. Morepreferred such unsubstituted alkyl groups have from 1 to 10 carbon atomswhile even more preferred such groups have from 1 to 5 carbon atoms.Most preferred unsubstituted alkyl groups include straight and branchedchain alkyl groups having from 1 to 3 carbon atoms and include methyl,ethyl, propyl, and —CH(CH₃)₂.

[0076] The phrase “substituted alkyl” refers to an unsubstituted alkylgroup as defined above in which one or more bonds to a carbon(s) orhydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atomssuch as, but not limited to, a halogen atom in halides such as F, Cl,Br, and I; and oxygen atom in groups such as hydroxyl groups, alkoxygroups, aryloxy groups, and ester groups; a sulfur atom in groups suchas thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonylgroups, and sulfoxide groups; a nitrogen atom in groups such as amines,amides, alkylamines, dialkylamines, arylamines, alkylarylamines,diarylamines, N-oxides, imides, and enamines; a silicon atom in groupssuch as in trialkylsilyl groups, dialkylarylsilyl groups,alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatomsin various other groups. Substituted alkyl groups also include groups inwhich one or more bonds to a carbon(s) or hydrogen(s) atom is replacedby a bond to a heteroatom such as oxygen in carbonyl, carboxyl, andester groups; nitrogen in groups such as imines, oximes, hydrazones, andnitriles. Substituted alkyl groups include, among others, alkyl groupsin which one or more bonds to a carbon or hydrogen atom is/are replacedby one or more bonds to fluorine atoms. One Example of a substitutedalkyl group is the trifluoromethyl group and other alkyl groups thatcontain the trifluoromethyl group. Other alkyl groups include those inwhich one or more bonds to a carbon or hydrogen atom is replaced by abond to an oxygen atom such that the substituted alkyl group contains ahydroxyl, alkoxy, aryloxy, or heterocyclyloxy group. Still othersubstituted alkyl groups include alkyl groups that have an amine,alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine,heterocyclylamine, (alkyl)(heterocyclyl)amine,(aryl)(heterocyclyl)amine, or diheterocyclylamine group.

[0077] The phrase “unsubstituted aryl” refers to aryl groups that do notcontain heteroatoms. Thus the phrase includes, but is not limited to,groups such as phenyl, biphenyl, anthracenyl, naphthenyl by way ofexample. Although the phrase “unsubstituted aryl” includes groupscontaining condensed rings such as naphthalene, it does not include arylgroups that have other groups such as alkyl or halo groups bonded to oneof the ring members, as aryl groups such as tolyl are considered hereinto be substituted aryl groups as described below. A preferredunsubstituted aryl group is phenyl. Unsubstituted aryl groups may bebonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s),and/or sulfur atom(s) in the parent compound, however.

[0078] The phrase “substituted aryl group” has the same meaning withrespect to unsubstituted aryl groups that substituted alkyl groups hadwith respect to unsubstituted alkyl groups. However, a substituted arylgroup also includes aryl groups in which one of the aromatic carbons isbonded to one of the non-carbon or non-hydrogen atoms described aboveand also includes aryl groups in which one or more aromatic carbons ofthe aryl group is bonded to a substituted and/or unsubstituted alkylgroup. Thus, the phrase “substituted aryl” includes, but is not limitedto tolyl, and hydroxyphenyl among others.

[0079] The phrase “unsubstituted alkenyl” refers to straight andbranched chain and cyclic groups such as those described with respect tounsubstituted alkyl groups as defined above, except that at least onedouble bond exists between two carbon atoms. Examples include, but arenot limited to vinyl, —CH═C(H)(CH₃), —CH═C(CH₃)₂, —C(CH₃)═C(H)₂,—C(CH₃)═C(H)(CH₃), —C(CH₂CH₃)═CH₂, cyclohexenyl, cyclopentenyl,cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

[0080] The phrase “substituted alkenyl” has the same meaning withrespect to unsubstituted alkenyl groups that substituted alkyl groupshad with respect to unsubstituted alkyl groups. A substituted alkenylgroup includes alkenyl groups in which a non-carbon or non-hydrogen atomis bonded to a carbon double bonded to another carbon and those in whichone of the non-carbon or non-hydrogen atoms is bonded to a carbon notinvolved in a double bond to another carbon.

[0081] The phrase “unsubstituted alkynyl” refers to straight andbranched chain groups such as those described with respect tounsubstituted alkyl groups as defined above, except that at least onetriple bond exists between two carbon atoms. Examples include, but arenot limited to —C≡C(H), —C≡C(CH₃), —C≡C(CH₂CH₃), —C(H₂)C≡C(H),—C(H)₂C≡C(CH₃), and —C(H)₂C≡C(CH₂CH₃) among others.

[0082] The phrase “substituted alkynyl” has the same meaning withrespect to unsubstituted alkynyl groups that substituted alkyl groupshad with respect to unsubstituted alkyl groups. A substituted alkynylgroup includes alkynyl groups in which a non-carbon or non-hydrogen atomis bonded to a carbon triple bonded to another carbon and those in whicha non-carbon or non-hydrogen atom is bonded to a carbon not involved ina triple bond to another carbon.

[0083] The phrase “unsubstituted aralkyl” refers to unsubstituted alkylgroups as defined above in which a hydrogen or carbon bond of theunsubstituted alkyl group is replaced with a bond to an aryl group asdefined above. For example, methyl (—CH₃) is an unsubstituted alkylgroup. If a hydrogen atom of the methyl group is replaced by a bond to aphenyl group, such as if the carbon of the methyl were bonded to acarbon of benzene, then the compound is an unsubstituted aralkyl group(i.e. a benzyl group). Thus the phrase includes, but is not limited to,groups such as benzyl, diphenylmethyl, and 1-phenylethyl(—CH(C₆H₅)(CH₃)) among others.

[0084] The phrase “substituted aralkyl” has the same meaning withrespect to unsubstituted aralkyl groups that substituted aryl groups hadwith respect to unsubstituted aryl groups. However, a substitutedaralkyl group also includes groups in which a carbon or hydrogen bond ofthe alkyl part of the group is replaced by a bond to a non-carbon or anon-hydrogen atom. Examples of substituted aralkyl groups include, butare not limited to, —CH₂C(═O)(C₆H₅), and —CH₂(2-methylphenyl) amongothers.

[0085] The phrase “unsubstituted heterocyclyl” refers to both aromaticand nonaromatic ring compounds including monocyclic, bicyclic, andpolycyclic ring compounds such as, but not limited to, quinuclidyl,containing 3 or more ring members of which one or more is a heteroatomsuch as, but not limited to, N, O, and S. Although the phrase“unsubstituted heterocyclyl” includes condensed heterocyclic rings suchas benzimidazolyl, it does not include heterocyclyl groups that haveother groups such as alkyl or halo groups bonded to one of the ringmembers as compounds such as 2-methylbenzimidazolyl are substitutedheterocyclyl groups. Examples of heterocyclyl groups include, but arenot limited to: unsaturated 3 to 8 membered rings containing 1 to 4nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl,imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl etc.), tetrazolyl, (e.g. 1H-tetrazolyl,2H-tetrazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 4nitrogen atoms such as, but not limited to, pyrrolidinyl,imidazolidinyl, piperidinyl, piperazinyl; condensed unsaturatedheterocyclic groups containing 1 to 4 nitrogen atoms such as, but notlimited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl; unsaturated 3 to 8membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atomssuch as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (e.g.1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.);saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to3 nitrogen atoms such as, but not limited to, morpholinyl; unsaturatedcondensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl(e.g. 2H-1,4-benzoxazinyl etc.); unsaturated 3 to 8 membered ringscontaining 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, butnot limited to, thiazolyl, isothiazolyl, thiadiazolyl (e.g.1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.); saturated 3 to 8 membered rings containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to,thiazolodinyl; saturated and unsaturated 3 to 8 membered ringscontaining 1 to 2 sulfur atoms such as, but not limited to, thienyl,dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene,tetrahydrothiopyran; unsaturated condensed heterocyclic rings containing1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limitedto, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g.2H-1,4-benzothiazinyl, etc.), dihydrobenzothiazinyl (e.g.2H-3,4-dihydrobenzothiazinyl, etc.), unsaturated 3 to 8 membered ringscontaining oxygen atoms such as, but not limited to furyl; unsaturatedcondensed heterocyclic rings containing 1 to 2 oxygen atoms such asbenzodioxolyl (e.g. 1,3-benzodioxoyl, etc.); unsaturated 3 to 8 memberedrings containing an oxygen atom and 1 to 2 sulfur atoms such as, but notlimited to, dihydrooxathiinyl; saturated 3 to 8 membered ringscontaining 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as1,4-oxathiane; unsaturated condensed rings containing 1 to 2 sulfuratoms such as benzothienyl, benzodithiinyl; and unsaturated condensedheterocyclic rings containing an oxygen atom and 1 to 2 oxygen atomssuch as benzoxathiinyl. Heterocyclyl group also include those describedabove in which one or more S atoms in the ring is double bonded to oneor two oxygen atoms (sulfoxides and sulfones). For example, heterocyclylgroups include tetrahydrothiophene, tetrahydrothiophene oxide, andtetrahydrothiophene 1,1-dioxide. Preferred heterocyclyl groups contain 5or 6 ring members. More preferred heterocyclyl groups includemorpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole,1,2,3—triazole, 1,2,4-triazole, tetrazole, thiomorpholine, pyrrole,homopiperazine, oxazolidin-2—one, pyrrolidin-2-one, oxazole, thiazole,isoxazole, furan, and tetrahydrofuran.

[0086] The phrase “substituted heterocyclyl” refers to an unsubstitutedheterocyclyl group as defined above in which one of the ring members isbonded to a non-hydrogen atom such as described above with respect tosubstituted alkyl groups and substituted aryl groups. Examples, include,but are not limited to, 2-methylbenzimidazolyl, 5-methylbenzimidazolyl,5-chlorobenzthiazolyl, 1-methyl piperazinyl, and 2-chloropyridyl amongothers.

[0087] The phrase “unsubstituted heterocyclylalkyl” refers tounsubstituted alkyl groups as defined above in which a hydrogen orcarbon bond of the unsubstituted alkyl group is replaced with a bond toa heterocyclyl group as defined above. For example, methyl (—CH₃) is anunsubstituted alkyl group. If a hydrogen atom of the methyl group isreplaced by a bond to a heterocyclyl group, such as if the carbon of themethyl were bonded to carbon 2 of pyridine (one of the carbons bonded tothe N of the pyridine) or carbons 3 or 4 of the pyridine, then thecompound is an unsubstituted heterocyclylalkyl group.

[0088] The phrase “substituted heterocyclylalkyl” has the same meaningwith respect to unsubstituted heterocyclylalkyl groups that substitutedaralkyl groups had with respect to unsubstituted aralkyl groups.However, a substituted heterocyclylalkyl group also includes groups inwhich a non-hydrogen atom is bonded to a heteroatom in the heterocyclylgroup of the heterocyclylalkyl group such as, but not limited to, anitrogen atom in the piperidine ring of a piperidinylalkyl group.

[0089] The phrase “unsubstituted alkylaminoalkyl” refers to anunsubstituted alkyl group as defined above in which a carbon or hydrogenbond is replaced by a bond to a nitrogen atom that is bonded to ahydrogen atom and an unsubstituted alkyl group as defined above. Forexample, methyl (—CH₃) is an unsubstituted alkyl group. If a hydrogenatom of the methyl group is replaced by a bond to a nitrogen atom thatis bonded to a hydrogen atom and an ethyl group, then the resultingcompound is —CH₂—N(H)(CH₂CH₃) which is an unsubstituted alkylaminoalkylgroup.

[0090] The phrase “substituted alkylaminoalkyl” refers to anunsubstituted alkylaminoalkyl group as defined above except where one ormore bonds to a carbon or hydrogen atom in one or both of the alkylgroups is replaced by a bond to a non-carbon or non-hydrogen atom asdescribed above with respect to substituted alkyl groups except that thebond to the nitrogen atom in all alkylaminoalkyl groups does not byitself qualify all alkylaminoalkyl groups as being substituted. However,substituted alkylaminoalkyl groups does include groups in which thehydrogen bonded to the nitrogen atom of the group is replaced with anon-carbon and non-hydrogen atom.

[0091] The phrase “unsubstituted dialkylaminoalkyl” refers to anunsubstituted alkyl group as defined above in which a carbon bond orhydrogen bond is replaced by a bond to a nitrogen atom which is bondedto two other similar or different unsubstituted alkyl groups as definedabove.

[0092] The phrase “substituted dialkylaminoalkyl” refers to anunsubstituted dialkylaminoalkyl group as defined above in which one ormore bonds to a carbon or hydrogen atom in one or more of the alkylgroups is replaced by a bond to a non-carbon and non-hydrogen atom asdescribed with respect to substituted alkyl groups. The bond to thenitrogen atom in all dialkylaminoalkyl groups does not by itself qualifyall dialkylaminoalkyl groups as being substituted.

[0093] The phrase “unsubstituted heterocyclyloxyalkyl” refers to anunsubstituted alkyl group as defined above in which a carbon bond orhydrogen bond is replaced by a bond to an oxygen atom which is bonded toan unsubstituted heterocyclyl group as defined above.

[0094] The phrase “substituted heterocyclyloxyalkyl” refers to anunsubstituted heterocyclyloxyalkyl group as defined above in which abond to a carbon or hydrogen group of the alkyl group of theheterocyclyloxyalkyl group is bonded to a non-carbon and non-hydrogenatom as described above with respect to substituted alkyl groups or inwhich the heterocyclyl group of the heterocyclyloxyalkyl group is asubstituted heterocyclyl group as defined above.

[0095] The phrase “unsubstituted arylaminoalkyl” refers to anunsubstituted alkyl group as defined above in which a carbon bond orhydrogen bond is replaced by a bond to a nitrogen atom which is bondedto at least one unsubstituted aryl group as defined above.

[0096] The phrase “substituted arylaminoalkyl” refers to anunsubstituted arylaminoalkyl group as defined above except where eitherthe alkyl group of the arylaminoalkyl group is a substituted alkyl groupas defined above or the aryl group of the arylaminoalkyl group is asubstituted aryl group except that the bonds to the nitrogen atom in allarylaminoalkyl groups does not by itself qualify all arylaminoalkylgroups as being substituted. However, substituted arylaminoalkyl groupsdoes include groups in which the hydrogen bonded to the nitrogen atom ofthe group is replaced with a non-carbon and non-hydrogen atom.

[0097] The phrase “unsubstituted heterocyclylaminoalkyl” refers to anunsubstituted alkyl group as defined above in which a carbon or hydrogenbond is replaced by a bond to a nitrogen atom which is bonded to atleast one unsubstituted heterocyclyl group as defined above.

[0098] The phrase “substituted heterocyclylaminoalkyl” refers tounsubstituted heterocyclylaminoalkyl groups as defined above in whichthe heterocyclyl group is a substituted heterocyclyl group as definedabove and/or the alkyl group is a substituted alkyl group as definedabove. The bonds to the nitrogen atom in all heterocyclylaminoalkylgroups does not by itself qualify all heterocyclylaminoalkyl groups asbeing substituted. However, substituted heterocyclylaminoalkyl groups doinclude groups in which the hydrogen bonded to the nitrogen atom of thegroup is replaced with a non-carbon and non-hydrogen atom.

[0099] The phrase “unsubstituted alkylaminoalkoxy” refers to anunsubstituted alkyl group as defined above in which a carbon or hydrogenbond is replaced by a bond to an oxygen atom which is bonded to theparent compound and in which another carbon or hydrogen bond of theunsubstituted alkyl group is bonded to a nitrogen atom which is bondedto a hydrogen atom and an unsubstituted alkyl group as defined above.

[0100] The phrase “substituted alkylaminoalkoxy” refers to unsubstitutedalkylaminoalkoxy groups as defined above in which a bond to a carbon orhydrogen atom of the alkyl group bonded to the oxygen atom which isbonded to the parent compound is replaced by one or more bonds to anon-carbon and non-hydrogen atoms as discussed above with respect tosubstituted alkyl groups and/or if the hydrogen bonded to the aminogroup is bonded to a non-carbon and non-hydrogen atom and/or if thealkyl group bonded to the nitrogen of the amine is bonded to anon-carbon and non-hydrogen atom as described above with respect tosubstituted alkyl groups. The presence of the amine and alkoxyfunctionality in all alkylaminoalkoxy groups does not by itself qualifyall such groups as substituted alkylaminoalkoxy groups.

[0101] The phrase “unsubstituted dialkylaminoalkoxy” refers to anunsubstituted alkyl group as defined above in which a carbon or hydrogenbond is replaced by a bond to an oxygen atom which is bonded to theparent compound and in which another carbon or hydrogen bond of theunsubstituted alkyl group is bonded to a nitrogen atom which is bondedto two other similar or different unsubstituted alkyl groups as definedabove.

[0102] The phrase “substituted dialkylaminoalkoxy” refers to anunsubstituted dialkylaminoalkoxy group as defined above in which a bondto a carbon or hydrogen atom of the alkyl group bonded to the oxygenatom which is bonded to the parent compound is replaced by one or morebonds to a non-carbon and non-hydrogen atoms as discussed above withrespect to substituted alkyl groups and/or if one or more of the alkylgroups bonded to the nitrogen of the amine is bonded to a non-carbon andnon-hydrogen atom as described above with respect to substituted alkylgroups. The presence of the amine and alkoxy functionality in alldialkylaminoalkoxy groups does not by itself qualify all such groups assubstituted dialkylaminoalkoxy groups.

[0103] The phrase “unsubstituted heterocyclyloxy” refers to a hydroxylgroup (—OH) in which the bond to the hydrogen atom is replaced by a bondto a ring atom of an otherwise unsubstituted heterocyclyl group asdefined above.

[0104] The phrase “substituted heterocyclyloxy” refers to a hydroxylgroup (—OH) in which the bond to the hydrogen atom is replaced by a bondto a ring atom of an otherwise substituted heterocyclyl group as definedabove.

[0105] The term “protected” with respect to hydroxyl groups, aminegroups, and sulfhydryl groups refers to forms of these functionalitieswhich are protected from undesirable reaction with a protecting groupknown to those skilled in the art such as those set forth in ProtectiveGroups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley &Sons, New York, N.Y., (3rd Edition, 1999) which can be added or removedusing the procedures set forth therein. Examples of protected hydroxylgroups include, but are not limited to, silyl ethers such as thoseobtained by reaction of a hydroxyl group with a reagent such as, but notlimited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane,triisopropylchlorosilane, triethylchlorosilane; substituted methyl andethyl ethers such as, but not limited to methoxymethyl ether,methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether,2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethylether, allyl ether, benzyl ether; esters such as, but not limited to,benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.Examples of protected amine groups include, but are not limited to,amides such as, formamide, acetamide, trifluoroacetamide, and benzamide;imides, such as phthalimide, and dithiosuccinimide; and others. Examplesof protected sulfhydryl groups include, but are not limited to,thioethers such as S-benzyl thioether, and S-4-picolyl thioether;substituted S-methyl derivatives such as hemithio, dithio and aminothioacetals; and others.

[0106] A “pharmaceutically acceptable salt” includes a salt with aninorganic base, organic base, inorganic acid, organic acid, or basic oracidic amino acid. As salts of inorganic bases, the invention includes,for example, alkali metals such as sodium or potassium; alkaline earthmetals such as calcium and magnesium or aluminum; and ammonia. As saltsof organic bases, the invention includes, for example, trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine, andtriethanolamine. As salts of inorganic acids, the instant inventionincludes, for example, hydrochloric acid, hydroboric acid, nitric acid,sulfuric acid, and phosphoric acid. As salts of organic acids, theinstant invention includes, for example, formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, and p-toluenesulfonic acid. As salts of basicamino acids, the instant invention includes, for example, arginine,lysine and ornithine. Acidic amino acids include, for example, asparticacid and glutamic acid.

[0107] Compounds having the structure I, tautomers of the compounds,pharmaceutically acceptable salts of the compounds, and pharmaceuticallyacceptable salts of the tautomers have been found to inhibit VEGF-RTK.Structure I has the following formula.

[0108] In compounds of structure I, Y is selected from —OH, —OR⁸ groups,—SH, —SR⁹ groups, —NR¹⁰R¹¹ groups, —CN, —C(═O)—R¹² groups, substitutedor unsubstituted alkyl groups, substituted or unsubstituted alkenylgroups, substituted or unsubstituted alkynyl groups, substituted orunsubstituted aralkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkylgroups, substituted or unsubstituted dialkylaminoalkyl groups,substituted or unsubstituted arylaminoalkyl groups, substituted orunsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups. In more preferred compounds having thestructure I, Y is —OH, an —OR⁸ group, or a —NR¹⁰R¹¹ group. Morepreferably, Y is a —NR¹⁰R¹¹ group, where, one of R¹⁰ or R¹¹ is H orwhere R¹⁰ and R¹¹ are both H.

[0109] In yet other compounds having the structure I, Y is selected from—N(CH₃)₂, —NH(CH₃), —NH(CH₂CH₃), —N(CH₂CH₃)₂, —NH(aryl) groups,—N(aryl)₂ groups, —NHNH₂, —NHN(CH₃)₂, —N(CH₃)NH(CH₃), —NH(CH₂)_(m)NH₂groups, —NH(CH₂)_(m)NH(alkyl) groups, —NH(CH₂)_(m)N(alkyl)₂ groups,—N(alkyl)(CH₂)_(m)NH₂ groups, —N(alkyl)(CH₂)_(m)NH(alkyl) groups,—N(alkyl)(CH₂)_(m)N(alkyl)₂ groups, —NH(CH₂)_(n)(heterocyclyl) groups,—N(alkyl)[(CH₂)_(n)(heterocyclyl)] groups, —NH(CH₂)_(m)OH groups,—NH(CH₂)_(m)OCH₃ groups, —NHCH₂CH(NH₂)CH(CH₃)₂, —NH(2-aminocyclohexyl),—NH(cyclohexyl), —NHOCH₃, —NH(N-morpholinyl), —NH(quinuclidyl),especially —NH(quinuclid-3-yl), and groups where R¹⁰ and R¹¹ join toform a substituted or unsubstituted saturated 5 or 6 memberedN-containing ring, where m is 2, 3, or 4 and n is 0, 1, 2, or 3. Stillmore preferred compounds of this type are compounds in which Y is—NH(5-benzimidazolyl), —NH(CH₂)₂N(CH₃)₂, —NH(CH₂)₂OH,—NH(CH₂)(4-imidazolyl), —NH(CH₂)(3-imidazolyl), —NH(CH₂)(4-pyridyl),—NH(CH₂)(2-pyridyl), —NH(CH₂)(3-pyridyl), —NH(CH₂)(2-tetrahydrofuranyl),—NH(CH₂)(4-piperidinyl), —NH(CH₂)(3-piperidinyl),—NH(CH₂)₂[2-(N-methyl-pyrrolidinyl)], —NH(CH₂)₂(2-pyrrolidinyl),—NH(CH₂)[2-(N-methylpyrrolidinyl)], —NH(CH₂)(2-pyrrolidinyl),—NH(3-piperidinyl), or —NH(3-pyrrolidinyl).

[0110] Z is O, S, or a NR¹³ group in compounds of structure I.Preferably, Z is a NR¹³ group and, even more preferably, R¹³ is H.

[0111] In compounds of structure I, R¹ and R² join to form a 5 to 7membered substituted or unsubstituted ring including at least one O, N,or S atom. In some embodiments, R¹ and R² join together to form a 5 or 6membered substituted or unsubstituted ring including one N atom, one Oatom, or one S atom. In other embodiments R¹ and R² join together toform a 5 or 6 membered ring including two heteroatoms selected from O,N, or S. An example of an embodiment in which R¹ and R² join together toform a 5 membered ring having two N atoms are compounds having theformula IA described below. Another example of an embodiment in which R¹and R² join together to form a 5 membered ring having two N atoms arecompounds having the formula IB described below. An example of anembodiment in which R¹ and R² form a 5 membered ring having one S atomare compounds having the formula IC described below. Examples ofembodiments in which R¹ and R² join together to form a 6 membered ringcontaining one or more N atom are compounds having the formula II below.

[0112] R³ and R¹³ may be the same or different in compounds of structureI and may be H, —OH, substituted or unsubstituted alkoxy groups,substituted or unsubstituted aryloxy groups, —NH₂, substituted orunsubstituted alkylamino groups, substituted or unsubstituted arylaminogroups, substituted or unsubstituted dialkylamino groups, substituted orunsubstituted diarylamino groups, substituted or unsubstituted(alkyl)(aryl)amino groups, substituted and unsubstitutedheterocyclylamino groups, substituted and unsubstituteddiheterocyclylamino groups, substituted and unsubstituted(alkyl)(heterocyclyl)amino groups, substituted and unsubstituted(aryl)(heterocyclyl)amino groups, substituted and unsubstitutedheterocylyloxy groups, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —C(═O)H, —C(═O)-alkyl groups,or —C(═O)-aryl groups. In more preferred compounds of structure I, R³ isH.

[0113] R⁴, R⁵, R⁶, and R⁷ may be the same or different in compounds ofstructure I and are independently selected from H, Cl, Br, F, I, —NO₂,—CN, —OH, —OR¹⁴ groups, —NR¹⁵R¹⁶ groups, —C(═O)R¹⁷ groups, —SH, —SR¹⁸groups, —S(═O)R¹⁹ groups, S(═O)₂R²⁰ groups, substituted or unsubstitutedamidinyl groups, substituted or unsubstituted guanidinyl groups,substituted or unsubstituted primary, secondary, or tertiary alkylgroups, substituted or unsubstituted aryl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substitutedor unsubstituted heterocyclylalkyl groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkylgroups, substituted and unsubstituted diheterocyclylaminoalkyl groups,substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups,substituted and unsubstituted (aryl)(heterocyclyl)aminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups. R⁴ and R⁵ may join to form a 5 to 7membered substituted or unsubstituted carbocyclic or heterocyclic ring.Similarly, R⁵ and R⁶ may join to form a 5 to 7 membered substituted orunsubstituted carbocyclic or heterocyclic ring. Finally, R⁶ and R⁷ mayalso join to form a 5 to 7 membered substituted or unsubstitutedcarbocyclic or heterocyclic ring.

[0114] In one group of preferred compounds of structure I, R⁴, R⁵, R⁶,and R⁷ are all H. In other more preferred compounds of structure I, R⁵,R⁶ or both R⁵ and R⁶ are alkyl groups having from one to four carbonatoms. In still other preferred compounds having the formula ofstructure I, R⁵ or R⁶ is an —OR¹⁴ group and R¹⁴ is an alkyl, aryl,heterocyclyl, or heterocyclylalkyl group. In still further preferredcompounds of structure I, R⁵ or R⁶ is a —OCH₂(CH₂)_(q)(heterocyclyl)group where q is 0, 1, 2, 3, or 4. More preferably the heterocyclylgroup of the —OCH₂(CH₂)_(q)(heterocyclyl) group is a heterocycleselected from substituted or unsubstituted morpholine, substituted orunsubstituted piperazine, substituted or unsubstituted piperidine,substituted or unsubstituted pyrrolidine, substituted or unsubstitutedpyrrole, substituted or unsubstituted imidazole, substituted orunsubstituted pyrazole, substituted or unsubstituted 1,2,3-triazole,substituted or unsubstituted 1,2,4-triazole, substituted orunsubstituted tetrazole, substituted or unsubstituted thiomorpholine,substituted or unsubstituted homopiperazine, substituted orunsubstituted oxazolidin-2-one, substituted or unsubstitutedpyrrolidin-2-one, substituted or unsubstituted pyridine, substituted orunsubstituted oxazole, substituted or unsubstituted isoxazole,substituted or unsubstituted thiazole, substituted or unsubstitutedisothiazole, substituted or unsubstituted furan, substituted orunsubstituted thiophene, substituted or unsubstituted tetrahydrofuran,substituted or unsubstituted tetrahydrothiophene, substituted orunsubstituted benzimidazole, substituted or unsubstituted benzoxazole,or substituted or unsubstituted benzothiazole.

[0115] In still other preferred compounds having the structure I, atleast one of R⁴, R⁵, R⁶, or R⁷ is a substituted or unsubstitutedheterocyclyl group, more specifically a substituted or unsubstitutedheterocyclyl group comprising at least one O or N atom, and moreparticularly a substituted or unsubstituted heterocyclyl group selectedfrom morpholine, piperazine, piperidine, 1,2,3-triazole, 1,2,4-triazole,tetrazole, pyrrolidine, pyrazole, pyrrole, thiomorpholine,homopiperazine, benzimidazole, oxazolidin-2-one, pyrrolidin-2-one,imidazole, isoxazole, oxazole, isothiazole, thiazole, thiophene, furan,pyran, tetrahydrothiophene, tetrahydrofuran, tetrahydropyran, andpyridine.

[0116] In groups including heterocyclyl groups, the heterocycle may beattached in various ways. For example in the—OCH₂(CH₂)_(q)(heterocyclyl) group, the heterocyclyl group may be bondedto a methylene carbon of the —OCH₂(CH₂)_(q) group of the—OCH₂(CH₂)_(q)(heterocyclyl) group through various ring members. By wayof non-limiting example, where q is 1 and the heterocyclyl group istetrahydrofuran, the group could be represented by the formula—OCH₂CH₂-(tetrahydrofuranyl) which corresponds to the following twostructures:

[0117] where structure IV represents the group that can be referred toas the —OCH₂CH₂(2-tetrahydrofuranyl) group and structure V representsthe group that can be referred to as the —OCH₂CH₂(3-tetrahydrofuranyl)group. When the heterocyclyl group is a N-containing heterocycle, suchas, but not limited to piperidine, piperazine, morpholine, orpyrrolidine, the heterocycle can be bonded to the methylene carbonthrough a ring carbon atom or through a nitrogen atom in the ring of theN-containing heterocycle. Both of these are preferred. Where theheterocyclyl group is a piperidine and q is 2 for a—OCH₂(CH₂)_(q)(heterocyclyl) group, the following structures arepossible and preferred:

[0118] Structure VI is an example of a —O(CH₂)₃(N-piperidinyl) or—O(CH₂)₃(1-piperidinyl) group. Structure VII is an example of a—O(CH₂)₃(2-piperidinyl) group. Structure VIII is an example of a—O(CH₂)₃(3-piperidinyl) group. Structure IX is an example of a—O(CH₂)₃(4-piperidinyl) group. Where the heterocyclyl group is apiperazine and q is 1 for an —OCH₂(CH₂)_(q)(heterocyclyl) group, thefollowing structures are possible and preferred:

[0119] Structure X is an example of a —O(CH₂)₂(2-piperazinyl) group, andstructure XI is an example of a —O(CH₂)₂(1-piperazinyl) or—O(CH₂)₂(N-piperazinyl)group. Where the heterocyclyl group is amorpholine and q is 1 for an —OCH₂(CH₂)_(q)-(heterocyclyl) group, thefollowing structures are possible and preferred:

[0120] Structure XII is an example of a —O(CH₂)₂(3-morpholinyl) group,structure XIII is an example of a —O(CH₂)₂(4-morpholinyl) or—O(CH₂)₂(N-morpholinyl) group, and structure XIV is an example of a—O(CH₂)₂(2-morpholinyl) group. It will be observed that where the groupis a pyrrolidine, and q is 1, the structures available include—O(CH₂)₂(1-pyrrolidinyl) or —O(CH₂)₂(N-pyrrolidinyl),—O(CH₂)₂(2-pyrrolidinyl), and —O(CH₂)₂(3-pyrrolidinyl).

[0121] In compounds of structure I, R⁸ may be a substituted orunsubstituted alkyl group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heterocyclyl group, a substituted orunsubstituted heterocyclylalkyl group, —C(═O)H, a —C(═O)-alkyl group, a—C(═O)-aryl group, a —C(═O)O-alkyl group, a —C(═O)O-aryl group,—C(═O)NH₂, a —C(═O)NH(alkyl) group, a —C(═O)NH(aryl) group, a—C(═O)N(alkyl)₂ group, a —C(═O)N(aryl)₂ group, a —C(═O)N(alkyl)(aryl)group, —NH₂, a —NH(alkyl) group, a —NH(aryl) group, a —N(alkyl)₂ group,a —N(alkyl)(aryl) group, a —N(aryl)₂ group, a —C(═O)NH(heterocyclyl)group, a —C(═O)N(heterocyclyl)₂ group, a —C(═O)N(alkyl)(heterocyclyl)group, or a —C(═O)N(aryl)(heterocyclyl) group.

[0122] R⁹ and R¹⁸ may be the same or different in compounds of structureI and are independently selected from substituted or unsubstituted alkylgroups, or substituted or unsubstituted aryl groups.

[0123] In compounds of structure I, R¹⁰ is selected from H, substitutedor unsubstituted alkyl groups, substituted or unsubstituted aryl groups,or substituted or unsubstituted heterocyclyl groups, and R₁₁ is selectedfrom H, substituted or unsubstituted alkyl groups, substituted orunsubstituted aryl groups, substituted or unsubstituted heterocyclylgroups, —OH, alkoxy groups, aryloxy groups, —NH₂, substituted orunsubstituted heterocyclylalkyl groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups,substituted or unsubstituted dialkylaminoalkyl groups, substituted orunsubstituted arylaminoalkyl groups, substituted or unsubstituteddiarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylaminogroups, substituted or unsubstituted arylamino groups, substituted orunsubstituted dialkylamino groups, substituted or unsubstituteddiarylamino groups, substituted or unsubstituted (alkyl)(aryl)aminogroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted or unsubstitutedhydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups,substituted or unsubstituted aryloxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups. R¹⁰ and R¹¹ may join togetherto form a 5 to 7 membered saturated or unsaturated, substituted orunsubstituted N-containing ring.

[0124] In compounds of structure I, R¹² is selected from H, —OH, alkoxygroups, aryloxy groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups,—N(alkyl)₂ groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, substitutedor unsubstituted alkyl groups, substituted or unsubstituted aryl groups,—NH(heterocyclyl) groups, —N(heterocyclyl)₂ groups,—N(alkyl)(heterocyclyl) groups, or —N(aryl)(heterocyclyl) groups.

[0125] In structure I, R¹⁴ is selected from substituted or unsubstitutedalkyl groups, substituted or unsubstituted aryl groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstitutedheterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-arylgroups, —C(═O)-heterocyclyl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)NH-heterocyclyl groups,—C(═O)N-(heterocyclyl)₂ groups, —C(═O)N(alkyl)(heterocyclyl) groups,—C(═O)N(aryl)(heterocyclyl) groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups,substituted or unsubstituted dialkylaminoalkyl groups, substituted orunsubstituted arylaminoalkyl groups, substituted or unsubstituteddiarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituteddiheterocyclylaminoalkyl groups, substituted or unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedalkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups,substituted or unsubstituted hydroxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups.

[0126] In compounds of structure I, R¹⁵ is selected from H, substitutedor unsubstituted alkyl groups, substituted or unsubstituted aryl groups,or substituted or unsubstituted heterocyclyl groups. R¹⁶ is selectedfrom H, substituted or unsubstituted alkyl groups, substituted orunsubstituted aryl groups, substituted or unsubstituted heterocyclylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂,—C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups,—C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, substituted or unsubstituted aminoalkylgroups, substituted or unsubstituted alkylaminoalkyl groups, substitutedor unsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted or unsubstituted heterocyclylalkyl groups,—C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups,—C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)₂ groups,—C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl)groups, substituted or unsubstituted heterocyclylaminoalkyl groups,substituted and unsubstituted diheterocyclylaminoalkyl groups,substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups,substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups. R¹⁵ and R¹⁶ may join together to form a 5to 7 membered saturated or unsaturated, substituted or unsubstitutedN-containing ring.

[0127] R¹⁷, R¹⁹, and R²⁰ may be the same or different and areindependently selected from H, —NH₂, —NH(alkyl) groups, —NH(aryl)groups, —N(alkyl)₂ groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups,—NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups,—N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, substituted andunsubstituted alkyl groups, substituted and unsubstituted aryl groups,—OH, substituted and unsubstituted alkoxy groups, substituted andunsubstituted heterocyclyl groups, substituted and unsubstituted aryloxygroups, heterocyclyloxy groups, —NHOH, —N(alkyl)OH groups, —N(aryl)OHgroups, —N(alkyl)O-alkyl groups, —N(aryl)O-alkyl groups, —N(alkyl)O-arylgroups, and —N(aryl)O-aryl groups.

[0128] In some preferred compounds of structure I, R¹⁷ is selected fromunsubstituted alkyl groups, substituted or unsubstituted aryl groups,—NH₂, —NH(alkyl) groups, —N(alkyl)₂ groups, —NH(aryl) groups, —N(aryl)₂groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl) groups,—N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups,—N(heterocyclyl)₂ groups, or N-containing heterocycles, and theN-containing heterocycles are bonded to the carbonyl carbon of the—C(═O)—R¹⁷ group through either a nitrogen atom or a carbon atom in therings of the N-containing heterocycles. In still more preferredcompounds in which R¹⁷ is a N-containing heterocycle, the N-containingheterocycle of the R¹⁷ group is selected from substituted orunsubstituted morpholine, substituted or unsubstituted pyrrolidine,substituted or unsubstituted piperazine, substituted or unsubstitutedpiperidine, substituted or unsubstituted pyrrole, substituted orunsubstituted imidazole, substituted or unsubstituted pyrazole,substituted or unsubstituted 1,2,3-triazole, substituted orunsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole,substituted or unsubstituted thiomorpholine, substituted orunsubstituted homopiperazine, substituted or unsubstitutedoxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one,substituted or unsubstituted pyridine, substituted or unsubstitutedoxazole, substituted or unsubstituted isoxazole, substituted orunsubstituted thiazole, substituted or unsubstituted isothiazole,substituted or unsubstituted benzimidazole, substituted or unsubstitutedbenzoxazole, or substituted or unsubstituted benzothiazole.

[0129] In other preferred compounds having structure I, R¹⁴ or R¹⁶ isselected from substituted or unsubstituted aminoalkyl groups,substituted or unsubstituted alkylaminoalkyl groups, substituted orunsubstituted arylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, alkylarylaminoalkyl groups, or substituted or unsubstitutedheterocycylalkyl groups, including: —CH₂(CH₂)_(p)NH₂ groups,—CH₂(CH₂)_(p)NH(alkyl) groups, —CH₂(CH₂)_(p)NH(aryl) groups,—CH₂(CH₂)_(p)N(alkyl)₂ groups, —CH₂(CH₂)_(p)N(aryl)₂ groups,—CH₂(CH₂)_(p)N(alkyl)(aryl) groups, or —CH₂(CH₂)_(p)(heterocyclyl)groups, where p is an integer ranging from 0 to 4 and the heterocyclylgroup of the —CH₂(CH₂)_(p)(heterocyclyl) group is a N-containingheterocycle selected from substituted or unsubstituted morpholine,substituted or unsubstituted pyrrolidine, substituted or unsubstitutedpiperazine, substituted or unsubstituted piperidine, substituted orunsubstituted pyrrole, substituted or unsubstituted imidazole,substituted or unsubstituted pyrazole, substituted or unsubstituted1,2,3-triazole, substituted or unsubstituted 1,2,4-triazole, substitutedor unsubstituted tetrazole, substituted or unsubstituted thiomorpholine,substituted or unsubstituted homopiperazine, substituted orunsubstituted oxazolidin-2-one, substituted or unsubstitutedpyrrolidin-2-one, substituted or unsubstituted pyridine, substituted orunsubstituted oxazole, substituted or unsubstituted isoxazole,substituted or unsubstituted thiazole, substituted or unsubstitutedisothiazole, substituted or unsubstituted benzimidazole, substituted orunsubstituted benzoxazole, or substituted or unsubstitutedbenzothiazole.

[0130] Other compounds having the structure I are provided that alsohave the structure IA. These are compounds in which R¹ and R² ofstructure I join together to form a 5 membered ring having having two Natoms.

[0131] In compounds of structure IA, R²¹ is selected from H orsubstituted or unsubstituted alkyl groups; R²² may be the same ordifferent from R⁴, R⁵, R⁶, R⁷ and is independently selected from H, Cl,Br, F, I, —NO₂, —CN, —OH, —OR¹⁴ groups, —NR¹⁵R¹⁶ groups, —C(═O)R¹⁷groups, —SH, —SR¹⁸ groups, —S(═O)R¹⁹ groups, S(═O)₂R²⁰ groups,substituted or unsubstituted amidinyl groups, substituted orunsubstituted guanidinyl groups, substituted or unsubstituted primary,secondary, or tertiary alkyl groups, substituted or unsubstituted arylgroups, substituted or unsubstituted alkenyl groups, substituted orunsubstituted alkynyl groups, substituted or unsubstituted heterocyclylgroups, substituted or unsubstituted alkylaminoalkyl groups, substitutedor unsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted or unsubstituted heterocyclylalkyl groups, substituted orunsubstituted aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkylgroups, substituted or unsubstituted alkoxyalkyl groups, substituted orunsubstituted aryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups; and R³ through R²¹ have the valuesdescribed above with respect to compounds of structure I.

[0132] Other compounds of structure IA are those in which Z is an NR¹³and more preferably where R¹³ is H. Other compounds of structure IA areprovided in which R³ is H.

[0133] Still other compounds of structure IA are those in which Y is an—NR¹⁰R¹¹ group. In still other compounds of structure IA, Y is an—NR¹⁰R¹¹ group and R¹⁰ and R¹¹ are hydrogen atoms.

[0134] Still other compounds having the structure I are provided thathave the structure IB. Like compounds of structure IA, these arecompounds in which R¹ and R² of structure I join together to form a 5membered ring having having two N atoms.

[0135] In compounds of structure IB, R²¹ is selected from H orsubstituted or unsubstituted alkyl groups; R²² may be the same ordifferent from R⁴, R⁵, R⁶, R⁷ and is independently selected from H, Cl,Br, F, I, —NO₂, —CN, —OH, —OR¹⁴ groups, —NR¹⁵R¹⁶ groups, —C(═O)R¹⁷groups, —SH, —SR¹⁸ groups, —S(═O)R¹⁹ groups, S(═O)₂R²⁰ groups,substituted or unsubstituted amidinyl groups, substituted orunsubstituted guanidinyl groups, substituted or unsubstituted primary,secondary, or tertiary alkyl groups, substituted or unsubstituted arylgroups, substituted or unsubstituted alkenyl groups, substituted orunsubstituted alkynyl groups, substituted or unsubstituted heterocyclylgroups, substituted or unsubstituted alkylaminoalkyl groups, substitutedor unsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted or unsubstituted heterocyclylalkyl groups, substituted orunsubstituted aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkylgroups, substituted or unsubstituted alkoxyalkyl groups, substituted orunsubstituted aryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups; and R³ through R²¹ have the valuesdescribed above with respect to compounds of structure I.

[0136] Other compounds of structure IB include those in which Z is anNR¹³ and more preferably those where R¹³ is H. Other compounds ofstructure IB are those in which R³ is H.

[0137] Still other compounds of structure IB are those in which Y is an—NR¹⁰R¹¹ group. In still other compounds of structure IB, Y is an—NR¹⁰R¹¹ group and R¹⁰ and R¹¹ are hydrogen atoms.

[0138] Still other compounds having the structure I are provided thathave the structure IC. These are compounds in which R¹ and R² ofstructure I join together to form a 5 membered ring having having one Satom.

[0139] In compounds of structure IC, R²¹ and R²² may be the same ordifferent from R⁴, R⁵, R⁶, R⁷ and each other and are independentlyselected from H, Cl, Br, F, —NO₂, —CN, —OH, —OR¹⁴ groups, —NR¹⁵R¹⁶groups, —C(═O)R¹⁷ groups, —SH, —SR¹⁸ groups, —S(═O)R¹⁹ groups, S(═O)₂R²⁰groups, substituted or unsubstituted amidinyl groups, substituted orunsubstituted guanidinyl groups, substituted or unsubstituted primary,secondary, or tertiary alkyl groups, substituted or unsubstituted arylgroups, substituted or unsubstituted alkenyl groups, substituted orunsubstituted alkynyl groups, substituted or unsubstituted heterocyclylgroups, substituted or unsubstituted alkylaminoalkyl groups, substitutedor unsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted or unsubstituted heterocyclylalkyl groups, substituted orunsubstituted aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkylgroups, substituted or unsubstituted alkoxyalkyl groups, substituted orunsubstituted aryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups; and R³ through R²⁰ have the valuesdescribed above with respect to compounds of structure I.

[0140] Other compounds of structure IC are those in which Z is an NR¹³and more preferably those where R¹³ is H. Other compounds of structureIC are those in which R³ is H.

[0141] Still other compounds of structure IC are those in which Y is an—NR¹⁰R¹¹ group. In still other compounds of structure IC, Y is an—NR¹⁰R¹¹ group and R¹⁰ and R¹¹ are hydrogen atoms.

[0142] Particularly preferred inhibitors of VEGF-RTK are compoundshaving the structure II, tautomers of the compounds, pharmaceuticallyacceptable salts of the compounds, and pharmaceutically acceptable saltsof the tautomers. These are compounds having a ring system similar tothat of Structure I where R¹ and R², as defined above with respect toStructure I, join together to form a 6 membered ring that includes atleast one N atom. Structure II has the following formula:

[0143] In compounds of structure II, W¹, W², W³, and W⁴ are selectedfrom C or N, and at least one of W¹, W², W³, or W⁴ is N. In somepreferred compounds of structure II, W¹ is N and R¹ is absent or H. Inother preferred compounds of structure II, W² is N and R² is absent orH. In still other preferred compounds of structure II, W³ is N and R³ isabsent or H. In yet other preferred compounds of structure II, W⁴ is Nand R⁴ is absent or H. In some preferred compounds of structure II, oneof W¹, W², W³, and W⁴ is N. In other preferred compounds of structureII, two of W¹, W², W³, and W⁴ are N. In yet other preferred embodiments,W¹, W², and W³ are all C and W⁴ is N; W¹, W², and W⁴ are all C and W³ isN; W¹, W³, and W⁴ are all C and W² is N; or W², W³, and W⁴ are all C andW¹ is N.

[0144] In compounds having structure II, Y is selected from —OH, —OR¹⁰groups, —SH, —SR¹¹ groups, —NR¹²R¹³ groups, —CN, —C(═O)—R¹⁴ groups,substituted or unsubstituted alkyl groups, substituted or unsubstitutedalkenyl groups, substituted or unsubstituted alkynyl groups, substitutedor unsubstituted aralkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkylgroups, substituted or unsubstituted dialkylaminoalkyl groups,substituted or unsubstituted arylaminoalkyl groups, substituted orunsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups.

[0145] In preferred compounds of structure II, Y is selected from —OH,—OR¹⁰ groups, or —NR¹²R¹³ groups, or more preferably —NR¹²R¹³ groups, orstill more preferably —NR¹²R¹³ groups where one or both of R¹² and R¹³are H. In other preferred compounds having the structure II, Y isselected from —N(CH₃)₂, —NH(CH₃), —NH(CH₂CH₃), —N(CH₂CH₃)₂, —NH(aryl)groups, —N(aryl)₂ groups, —NHNH₂, —NHN(CH₃)₂, —N(CH₃)NH(CH₃),—NH(CH₂)_(m)NH₂ groups, —NH(CH₂)_(m)NH(alkyl) groups,—NH(CH₂)_(m)N(alkyl)₂ groups, —N(alkyl)(CH₂)_(m)NH₂ groups,—N(alkyl)(CH₂)_(m)NH(alkyl) groups, —N(alkyl)(CH₂)_(m)N(alkyl)₂ groups,—NH(CH₂)_(n)(heterocyclyl) groups, —N(alkyl)[(CH₂)_(n)(heterocyclyl)]groups, —NH(CH₂)_(m)OH groups, —NH(CH₂)_(m)OCH₃ groups,—NHCH₂CH(NH₂)CH(CH₃)₂, —NH(2-aminocyclohexyl), —NH(cyclohexyl), —NHOCH₃,—NH(N-morpholinyl), —NH(quinuclidyl), especially —NH(quinuclid-3-yl),andgroups where R¹² and R¹³ join to form a substituted or unsubstitutedsaturated 5 or 6 membered N-containing ring, where m is 2, 3, or 4 and nis 0, 1, 2, or 3. Still more preferred compounds of this type are thosein which Y is selected from —NH(5-benzimidazolyl), —NH(CH₂)₂N(CH₃)₂,—NH(CH₂)₂OH, —NH(CH₂)(4-imidazolyl), —NH(CH₂)(3-imidazolyl),—NH(CH₂)(4-pyridyl), —NH(CH₂)(2-pyridyl), —NH(CH₂)(3-pyridyl),—NH(CH₂)(2-tetrahydrofuranyl), —NH(CH₂)(4-piperidinyl),—NH(CH₂)(3-piperidinyl), —NH(CH₂)₂[2-(N-methyl-pyrrolidinyl)],—NH(CH₂)₂(2-pyrrolidinyl), —NH(CH₂)[2-(N-methylpyrrolidinyl)],—NH(CH₂)(2-pyrrolidinyl), —NH(3-piperidinyl), or —NH(3-pyrrolidinyl).

[0146] In compound of structure II, Z is O, S, and NR¹⁵ groups. Inpreferred compounds of structure II, Z is an NR¹⁵ group or morepreferably is an NR¹⁵ group where R¹⁵ is H.

[0147] In compounds of structure II, R¹, R², R³, R⁴, R, R⁶, R⁷, and R⁸may be the same or different and are independently selected from H, Cl,Br, F, I, —NO₂, —CN, —OH, —OR¹⁶ groups, —NR¹⁷R¹⁸ groups, —C(═O)R¹⁹groups, —SH, —SR²⁰ groups, —S(═O)R²¹ groups, S(═O)₂R²² groups,substituted or unsubstituted amidinyl groups, substituted orunsubstituted guanidinyl groups, substituted or unsubstituted primary,secondary, or tertiary alkyl groups, substituted or unsubstituted arylgroups, substituted or unsubstituted alkenyl groups, substituted orunsubstituted alkynyl groups, substituted or unsubstituted heterocyclylgroups, substituted or unsubstituted alkylaminoalkyl groups, substitutedor unsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (alkyl)(aryl) aminoalkyl groups,substituted or unsubstituted heterocyclylalkyl groups, substituted orunsubstituted aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted or unsubstitutedhydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups,substituted or unsubstituted aryloxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups, and R¹ is absent or H if W¹is N, R² is absent or H if W² is N, R³ is absent or H if W³ is N, and R⁴is absent or H if W⁴ is N.

[0148] Some preferred compounds have the structure II where at least oneof R¹, R², R³, R⁴, R⁵, R⁶, R⁷, or R⁸ is a substituted or unsubstitutedheterocyclyl group, and in more preferred embodiments, a substituted orunsubstituted heterocyclyl group selected from morpholine, piperazine,piperidine, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyrrolidine,pyrazole, pyrrole, thiomorpholine, homopiperazine, benzimidazole,oxazolidin-2-one, pyrrolidin-2-one, imidazole, isothiazole, thiazole,thiophene, furan, pyran, tetrahydrothiophene, tetrahydrofuran,tetrahydropyran, and pyridine.

[0149] Still other preferred compounds having structure II are those inwhich R¹, R², and R³ are H, and W⁴ is N. Still other compounds havingthe formula of structure II are provided in which R², R³, and R⁴ are H,and W¹ is N. Still other compounds having the formula of structure IIare provided in which R¹, R³, and R⁴ are H, and W² is N. Still othercompounds having the formula of structure II are provided in which R¹,R², and R⁴ are H, and W³ is N.

[0150] In other preferred compounds, R¹ or R² is selected from F, Cl,substituted or unsubstituted alkoxy groups, substituted or unsubstitutedheterocyclyloxy groups, substituted or unsubstituted heterocyclylalkoxygroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted alkyl-, heterocycyl-, or aryl-aminoalkyl groups,substituted or unsubstituted dialkyl- or diaryl-aminoalkyl groups,substituted or unsubstituted alkylarylaminoalkyl groups, substituted orunsubstituted alkyl- and aryl-aminoalkoxy groups, substituted orunsubstituted dialkyl- and diaryl-aminoalkoxy groups, or substituted orunsubstituted alkylarylaminoalkoxy groups. Particular examples include:—C(═O)N(alkyl)₂ groups, —OCH₂CH₂(N-morpholinyl), N-morpholinyl,—OCH₂CH₂N(alkyl)₂ groups, —OCH₂CH₂NH(alkyl) groups, —OCH₂CH₂NH₂,—OCH₂CH₂NH(aryl) groups, —OCH₂CH₂N(aryl)₂ groups, alkoxy groups,—OCH₂CH₂N(alkyl)(aryl) groups, —O(4-piperidinyl),—O[4—(1-alkyl)piperidinyl] groups, —OCH₂(2-pyridyl), —O(3-pyrrolidinyl),or —O[3—(1-alkyl)pyrrolidinyl] groups.

[0151] Still other preferred compounds include those in which R² isselected from F, Cl, —NO₂, substituted or unsubstituted alkoxy groups,substituted or unsubstituted heterocyclylalkoxy groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstituted alkyl-,heterocycyl-, or aryl-aminoalkyl groups, substituted or unsubstituteddialkyl- and diaryl-aminoalkyl groups, substituted or unsubstitutedalkylarylaminoalkyl groups, substituted or unsubstituted alkyl- andaryl-aminoalkoxy groups, substituted or unsubstituted dialkyl- anddiaryl-aminoalkoxy groups, substituted or unsubstitutedalkylarylaminoalkoxy groups. Particular examples include: —OCH₃,N-morpholinyl, —N-cis-dialkylmorpholinyl, —N-(4—alkyl)piperazinyl, or—OCH₂(2-pyridyl).

[0152] In yet preferred compounds having structure II, R⁵, R⁶, R⁷, andR⁸ are hydrogen. In still other more preferred compounds of structureII, R⁶, R⁷ or both R⁶ and R⁷ are alkyl groups having from one to fourcarbon atoms. In yet other preferred compounds of structure II, R⁶ or R⁷is an —OR¹⁶ group and R¹⁶ is an alkyl, aryl, heterocyclyl, orheterocyclylalkyl group. In still further preferred compounds ofstructure II, R⁶ or R⁷ is a —OCH₂(CH₂)_(q)(heterocyclyl) group and q is0, 1, 2, 3, or 4. In more preferred compounds in which R⁶ or R⁷ is a—OCH₂(CH₂)_(q)-(heterocyclyl) group, the heterocyclyl group of the—OCH₂(CH₂)_(n)(heterocyclyl) group is a heterocycle selected fromsubstituted or unsubstituted morpholine, substituted or unsubstitutedpiperazine, substituted or unsubstituted piperidine, substituted orunsubstituted pyrrolidine, substituted or unsubstituted pyrrole,substituted or unsubstituted imidazole, substituted or unsubstitutedpyrazole, substituted or unsubstituted 1,2,3-triazole, substituted orunsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole,substituted or unsubstituted thiomorpholine, substituted orunsubstituted homopiperazine, substituted or unsubstitutedoxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one,substituted or unsubstituted pyridine, substituted or unsubstitutedoxazole, substituted or unsubstituted isoxazole, substituted orunsubstituted thiazole, substituted or unsubstituted isothiazole,substituted or unsubstituted furan, substituted or unsubstitutedthiophene, substituted or unsubstituted tetrahydrofuran, substituted orunsubstituted tetrahydrothiophene, substituted or unsubstitutedbenzimidazole, substituted or unsubstituted benzoxazole, or substitutedor unsubstituted benzothiazole.

[0153] In compounds of structure II, R⁹ and R¹⁵ may be the same ordifferent and are selected from H, —OH, substituted or unsubstitutedalkoxy groups, substituted or unsubstituted aryloxy groups, —NH₂,substituted or unsubstituted alkylamino groups, substituted orunsubstituted arylamino groups, substituted or unsubstituteddialkylamino groups, substituted or unsubstituted diarylamino groups,substituted or unsubstituted (alkyl)(aryl)amino groups, substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups,—C(═O)H, —C(═O)-alkyl groups, or —C(═O)-aryl groups. In preferredcompounds of structure II, R⁹ is hydrogen.

[0154] In compounds of structure II, R¹⁰ is selected from substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups,—C(═O)-aryl groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups,—C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl)groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups,—N(alkyl)(aryl) groups, —N(aryl)₂ groups, —C(═O)NH(heterocyclyl) groups,—C(═O)N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups, or—C(═O)N(aryl)(heterocyclyl) groups.

[0155] R¹¹ and R²⁰ may be the same or different in compounds ofstructure II and are independently selected from substituted orunsubstituted alkyl groups, or substituted or unsubstituted aryl groups.

[0156] In compounds of structure II, R¹² is selected from H, substitutedor unsubstituted alkyl groups, substituted or unsubstituted aryl groups,or substituted or unsubstituted heterocyclyl groups whereas R¹³ isselected from H, substituted or unsubstituted alkyl groups, substitutedor unsubstituted aryl groups, substituted or unsubstituted heterocyclylgroups, —OH, alkoxy groups, aryloxy groups, —NH₂, substituted orunsubstituted heterocyclylalkyl groups, substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups,substituted or unsubstituted dialkylaminoalkyl groups, substituted orunsubstituted arylaminoalkyl groups, substituted or unsubstituteddiarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylaminogroups, substituted or unsubstituted arylamino groups, substituted orunsubstituted dialkylamino groups, substituted or unsubstituteddiarylamino groups, substituted or unsubstituted (alkyl)(aryl)aminogroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkylgroups, substituted or unsubstituted alkoxyalkyl groups, substituted orunsubstituted aryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups. R¹² and R¹³ may join together to form a 5to 7 membered saturated or unsaturated, substituted or unsubstitutedN-containing ring.

[0157] In compounds of structure II, R¹⁴ is selected from H, —OH, alkoxygroups, aryloxy groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups,—N(alkyl)₂ groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, substitutedor unsubstituted alkyl groups, substituted or unsubstituted aryl groups,—NH(heterocyclyl) groups, —N(heterocyclyl)₂ groups,—N(alkyl)(heterocyclyl) groups, or —N(aryl)(heterocyclyl) groups.

[0158] In compounds of structure II, R¹⁶ is selected from substituted orunsubstituted alkyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups,—C(═O)-aryl groups, —C(═O)-heterocyclyl groups, —C(═O)NH₂,—C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups,—C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups,—C(═O)NH-heterocyclyl groups, —C(═O)N-(heterocyclyl)₂ groups,—C(═O)N(alkyl)(heterocyclyl) groups, —C(═O)N(aryl)(heterocyclyl) groups,substituted or unsubstituted aminoalkyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substitutedor unsubstituted heterocyclylaminoalkyl groups, substituted orunsubstituted diheterocyclylaminoalkyl groups, substituted orunsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted orunsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups,or substituted or unsubstituted heterocyclyloxyalkyl groups.

[0159] In compounds of structure II, R¹⁷ is selected from H, substitutedor unsubstituted alkyl groups, substituted or unsubstituted aryl groups,or substituted or unsubstituted heterocyclyl groups whereas R¹⁸ isselected from H, substituted or unsubstituted alkyl groups, substitutedor unsubstituted aryl groups, substituted or unsubstituted heterocyclylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂,—C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups,—C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, substituted or unsubstituted aminoalkylgroups, substituted or unsubstituted alkylaminoalkyl groups, substitutedor unsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (aryl)(alkyl)aminoalkyl groups,substituted or unsubstituted heterocyclylalkyl groups,—C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups,—C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)₂ groups,—C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl)groups, substituted or unsubstituted heterocyclylaminoalkyl groups,substituted and unsubstituted diheterocyclylaminoalkyl groups,substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups,substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups. R¹⁷ and R¹⁸ may join together to form a 5to 7 membered saturated or unsaturated, substituted or unsubstitutedN-containing ring.

[0160] Finally, in compounds of structure II, R¹⁹, R²¹, and R²² may bethe same or different and are independently selected from H, —NH₂,—NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl) groups,—N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups,—N(heterocyclyl)₂ groups, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —OH, substituted orunsubstituted alkoxy groups, substituted or unsubstituted heterocyclylgroups, substituted or unsubstituted aryloxy groups, heterocyclyloxygroups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkylgroups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, or—N(aryl)O-aryl groups.

[0161] Preferred compounds having the structure II include those inwhich R¹⁹ is selected from substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —NH₂, —NH(alkyl) groups,—N(alkyl)₂ groups, —NH(aryl) groups, —N(aryl)₂ groups, —N(alkyl)(aryl)groups, —NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups,—N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, or N-containingheterocycles, and the N-containing heterocycles are bonded to thecarbonyl carbon of the —C(═O)—R¹⁹ group through either a nitrogen atomor a carbon atom in the rings of the N-containing heterocycles. In stillmore preferred compounds in which R¹⁹ is a N-containing heterocycle, theN-containing heterocycle of the R¹⁹ group is selected from substitutedor unsubstituted morpholine, substituted or unsubstituted pyrrolidine,substituted or unsubstituted piperazine, substituted or unsubstitutedpiperidine, substituted or unsubstituted pyrrole, substituted orunsubstituted imidazole, substituted or unsubstituted pyrazole,substituted or unsubstituted 1,2,3-triazole, substituted orunsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole,substituted or unsubstituted thiomorpholine, substituted orunsubstituted homopiperazine, substituted or unsubstitutedoxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one,substituted or unsubstituted pyridine, substituted or unsubstitutedoxazole, substituted or unsubstituted isoxazole, substituted orunsubstituted thiazole, substituted or unsubstituted isothiazole,substituted or unsubstituted benzimidazole, substituted or unsubstitutedbenzoxazole, or substituted or unsubstituted benzothiazole.

[0162] Other preferred compounds having structure II are provided inwhich R¹⁶ or R¹⁸ is selected from substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups,substituted or unsubstituted arylaminoalkyl groups, substituted orunsubstituted dialkylaminoalkyl groups, substituted or unsubstituteddiarylaminoalkyl groups, alkylarylaminoalkyl groups, or substituted orunsubstituted heterocycylalkyl groups, including: —CH₂(CH₂)_(p)NH₂groups, —CH₂(CH₂)_(p)NH(alkyl) groups, —CH₂(CH₂)_(p)NH(aryl) groups,—CH₂(CH₂)_(p)N(alkyl)₂ groups, —CH₂(CH₂)_(p)N(aryl)₂ groups,—CH₂(CH₂)_(p)N(alkyl)(aryl) groups, or —CH₂(CH₂)_(p)(heterocyclyl)groups, where p is an integer ranging from 0 to 4 and the heterocyclylgroup of the —CH₂(CH₂)_(p)(heterocyclyl) group is a N-containingheterocycle selected from substituted or unsubstituted morpholine,substituted or unsubstituted pyrrolidine, substituted or unsubstitutedpiperazine, substituted or unsubstituted piperidine, substituted orunsubstituted pyrrole, substituted or unsubstituted imidazole,substituted or unsubstituted pyrazole, substituted or unsubstituted1,2,3-triazole, substituted or unsubstituted 1,2,4-triazole, substitutedor unsubstituted tetrazole, substituted or unsubstituted thiomorpholine,substituted or unsubstituted homopiperazine, substituted orunsubstituted oxazolidin-2-one, substituted or unsubstitutedpyrrolidin-2-one, substituted or unsubstituted pyridine, substituted orunsubstituted oxazole, substituted or unsubstituted isoxazole,substituted or unsubstituted thiazole, substituted or unsubstitutedisothiazole, substituted or unsubstituted benzimidazole, substituted orunsubstituted benzoxazole, or substituted or unsubstitutedbenzothiazole.

[0163] Other particularly preferred inhibitors of VEGF-RTK are compoundshaving the structure III, tautomers of the compounds, pharmaceuticallyacceptable salts of the compounds, and pharmaceutically acceptable saltsof the tautomers. Structure III has the following formula:

[0164] In compounds of structure III, W¹, W², W³, and W⁴ are selectedfrom C or N, and at least one of W¹, W², W³, or W⁴ is N. In somepreferred compounds of structure III, W¹ is N and R¹ is absent or H. Inother preferred compounds of structure III, W² is N and R² is absent orH. In still other preferred compounds of structure III, W³ is N and R³is absent or H. In yet other preferred compounds of structure III, W⁴ isN and R⁴ is absent or H. In other preferred compounds of structure III,one of W¹, W², W³, and W⁴ is N whereas in other compounds of structureIII, two of W¹, W², W³, and W⁴ are N. In yet other preferredembodiments, W¹, W², and W³ are all C and W⁴ is N; W¹, W², and W⁴ areall C and W³ is N; W¹, W³, and W⁴ are all C and W² is N; or W², W³, andW⁴ are all C and W¹ is N.

[0165] In compounds of structure III, X¹, X², X³, and X⁴ are selectedfrom C or N, and at least one of X¹, X², X³, or X⁴ is N. In somepreferred compounds of structure III, X¹ is N and R⁵ is absent or H. Inother preferred compounds of structure III, X² is N and R⁶ is absent orH. In still other preferred compounds of structure III¹, X³ is N and R⁷is absent or H. In yet other preferred compounds of structure III, X⁴ isN and R⁸ is absent or H. In other preferred compounds of structure III,one of X¹, X², X³, and X⁴ is N whereas in other compounds of structureIII, two of X¹, X², X³, and X⁴ are N.

[0166] In compounds having structure III, Y is selected from H, —OH,—OR¹⁰ groups, —SH, —SR¹¹ groups, —NR¹²R¹³ groups, —CN, —C(═O)—R¹⁴groups, substituted or unsubstituted alkyl groups, substituted orunsubstituted alkenyl groups, substituted or unsubstituted alkynylgroups, substituted or unsubstituted aralkyl groups, substituted orunsubstituted heterocyclylalkyl groups, substituted or unsubstitutedalkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkylgroups, substituted or unsubstituted arylaminoalkyl groups, substitutedor unsubstituted diarylaminoalkyl groups, substituted or unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedheterocyclyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted hydroxyalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups.

[0167] In preferred compounds of structure III, Y is selected from H,OH, —OR¹⁰ groups, or —NR¹²R¹³ groups. More preferably, Y is a —NR¹²R¹³group. Still more preferably, Y is a —NR¹²R¹³ group and both R¹² and R¹³are hydrogen. In other preferred compounds having the structure III, Yis selected from —N(CH₃)₂, —NH(CH₃), —NH(CH₂CH₃), —N(CH₂CH₃)₂, —NH(aryl)groups, —N(aryl)₂ groups, —NHNH₂, —NHN(CH₃)₂, —N(CH₃)NH(CH₃),—NH(CH₂)_(m)NH₂ groups, —NH(CH₂)_(m)NH(alkyl) groups,—NH(CH2)_(m)N(alkyl)₂ groups, —N(alkyl)(CH₂)_(m)NH₂ groups,—N(alkyl)(CH₂)_(m)NH(alkyl) groups, —N(alkyl)(CH₂)_(m)N(alkyl)₂ groups,—NH(CH₂)_(n)(heterocyclyl) groups, —N(alkyl)[(CH₂)_(n)heterocyclyl)]groups, —NH(CH₂)_(m)OH groups, —NH(CH₂)_(m)OCH₃ groups,—NHCH₂CH(NH₂)CH(CH₃)₂, —NH(2-aminocyclohexyl), —NH(cyclohexyl), —NHOCH₃,—NH(N-morpholinyl), —NH(quinuclidyl), especially —NH(quinuclid-3-yl),and groups where R¹² and R¹³ join to form a substituted or unsubstitutedsaturated 5 or 6 membered N-containing ring, where m is 2, 3, or 4 and nis 0, 1, 2, or 3. Still more preferred compounds of this type are thosein which Y is selected from —NH(5-benzimidazolyl), —NH(CH₂)₂N(CH₃)₂,—NH(CH₂)₂OH, —NH(CH₂)(4-imidazolyl), —NH(CH₂)(3-imidazolyl),—NH(CH₂)(4-pyridyl), —NH(CH₂)(2-pyridyl), —NH(CH₂)(3-pyridyl),—NH(CH₂)(2-tetrahydrofuranyl), —NH(CH₂)(4-piperidinyl),—NH(CH₂)(3-piperidinyl), —NH(CH₂)₂[2-(N-methyl-pyrrolidinyl)],—NH(CH₂)₂(2-pyrrolidinyl), —NH(CH₂)[2-(N-methylpyrrolidinyl)],—NH(CH₂)(2-pyrrolidinyl), —NH(3-piperidinyl), or —NH(3-pyrrolidinyl).

[0168] In compounds of structure III, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸may be the same or different and are independently selected from H, Cl,Br, F, I, —NO₂, —CN, —OH, —OR¹⁵ groups, —NR¹⁶R¹⁷ groups, —C(═O)R¹⁸groups, —SH, —SR¹⁹ groups, —S(═O)R²⁰ groups, S(═O)₂R²¹ groups,substituted or unsubstituted amidinyl groups, substituted orunsubstituted guanidinyl groups, substituted or unsubstituted primary,secondary, or tertiary alkyl groups, substituted or unsubstituted arylgroups, substituted or unsubstituted alkenyl groups, substituted orunsubstituted alkynyl groups, substituted or unsubstituted heterocyclylgroups, substituted or unsubstituted alkylaminoalkyl groups, substitutedor unsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted or unsubstituted heterocyclylalkyl groups, substituted orunsubstituted aminoalkyl groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted or unsubstitutedhydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups,substituted or unsubstituted aryloxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups, and R¹ is absent or H if W¹is N, R² is absent or H if W² is N, R³ is absent or H if W³ is N, R⁴ isabsent or H if W⁴ is N, R⁵ is absent or H if X¹ is N, R⁶ is absent or Hif X² is N, R⁷ is absent or H if X³ is N, and R⁸ is absent or H if X⁴isN.

[0169] Some preferred compounds have the structure III where at leastone of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, or R⁸ is a substituted orunsubstituted heterocyclyl group selected from a group of heterocyclesthat includes morpholine, piperazine, piperidine, 1,2,3-triazole,1,2,4-triazole, tetrazole, pyrrolidine, pyrazole, pyrrole,thiomorpholine, homopiperazine, benzimidazole, oxazolidin-2-one,pyrrolidin-2-one, imidazole, isothiazole, thiazole, thiophene, furan,pyran, tetrahydrothiophene, tetrahydrofuran, tetrahydropyran, andpyridine.

[0170] Still other preferred compounds having structure III are those inwhich R¹, R², and R³ are H, and W⁴ is N. Still other compounds havingthe formula of structure III are provided in which R², R³, and R⁴ are H,and W¹ is N. Still other compounds having the formula of structure IIIare provided in which R¹, R³, and R⁴ are H, and W² is N. Still othercompounds having the formula of structure III are provided in which R¹,R², and R⁴ are H, and W³ is N.

[0171] In other preferred compounds, R¹ or R² is selected from F, Cl,substituted or unsubstituted alkoxy groups, substituted or unsubstitutedheterocyclyloxy groups, substituted or unsubstituted heterocyclylalkoxygroups, substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted alkyl-, heterocycyl-, or aryl-aminoalkyl groups,substituted or unsubstituted dialkyl- or diaryl-aminoalkyl groups,substituted or unsubstituted alkylarylaminoalkyl groups, substituted orunsubstituted alkyl- and aryl-aminoalkoxy groups, substituted orunsubstituted dialkyl- and diaryl-aminoalkoxy groups, or substituted orunsubstituted alkylarylaminoalkoxy groups. Particular examples include:—C(═O)N(alkyl)₂ groups, —OCH₂CH₂(N-morpholinyl), N-morpholinyl,—OCH₂CH₂N(alkyl)₂ groups, —OCH₂CH₂NH(alkyl) groups, —OCH₂CH₂NH_(2,)—OCH₂CH₂NH(aryl) groups, —OCH₂CH₂N(aryl)₂ groups, alkoxy groups,—OCH₂CH₂N(alkyl)(aryl) groups, —O(4-piperidinyl),—O[4-(1-alkyl)piperidinyl] groups, —OCH₂(2-pyridyl), —O(3-pyrrolidinyl),or —O[3-(1-alkyl)pyrrolidinyl] groups.

[0172] Still other preferred compounds include those in which R² isselected from F, Cl, —NO₂, substituted or unsubstituted alkoxy groups,substituted or unsubstituted heterocyclylalkoxy groups, substituted orunsubstituted heterocyclyl groups, substituted or unsubstituted alkyl-,heterocycyl-, or aryl-aminoalkyl groups, substituted or unsubstituteddialkyl- and diaryl-aminoalkyl groups, substituted or unsubstitutedalkylarylaminoalkyl groups, substituted or unsubstituted alkyl- andaryl-aminoalkoxy groups, substituted or unsubstituted dialkyl- anddiaryl-aminoalkoxy groups, substituted or unsubstitutedalkylarylaminoalkoxy groups. Particular examples include: —OCH₃,N-morpholinyl, —N-cis-dialkylmorpholinyl, —N-(4-alkyl)piperazinyl, or—OCH₂(2-pyridyl).

[0173] In yet preferred compounds having structure III, R⁵, R⁶, and R⁷are hydrogen, and X⁴ is N. In still other more preferred compounds ofstructure III, R⁶, R⁷ or both R⁶ and R⁷ are alkyl groups having from oneto four carbon atoms. In yet other preferred compounds of structure III,R⁶ or R⁷ is an —OR¹⁵ group and R¹⁵ is an alkyl, aryl, heterocyclyl, orheterocyclylalkyl group. In still further preferred compounds ofstructure III, R⁶ or R⁷ is a —OCH₂(CH₂)_(q)(heterocyclyl) group and q is0, 1, 2, 3, or 4. In more preferred compounds in which R⁶ or R⁷ is a—OCH₂(CH₂)_(q)-(heterocyclyl) group, the heterocyclyl group of the—OCH₂(CH₂)_(q)(heterocyclyl) group is a heterocycle selected fromsubstituted or unsubstituted morpholine, substituted or unsubstitutedpiperazine, substituted or unsubstituted piperidine, substituted orunsubstituted pyrrolidine, substituted or unsubstituted pyrrole,substituted or unsubstituted imidazole, substituted or unsubstitutedpyrazole, substituted or unsubstituted 1,2,3-triazole, substituted orunsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole,substituted or unsubstituted thiomorpholine, substituted orunsubstituted homopiperazine, substituted or unsubstitutedoxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one,substituted or unsubstituted pyridine, substituted or unsubstitutedoxazole, substituted or unsubstituted isoxazole, substituted orunsubstituted thiazole, substituted or unsubstituted isothiazole,substituted or unsubstituted furan, substituted or unsubstitutedthiophene, substituted or unsubstituted tetrahydrofuran, substituted orunsubstituted tetrahydrothiophene, substituted or unsubstitutedbenzimidazole, substituted or unsubstituted benzoxazole, or substitutedor unsubstituted benzothiazole.

[0174] In compounds of structure III, R⁹ is selected from H, —OH,substituted or unsubstituted alkoxy groups, substituted or unsubstitutedaryloxy groups, —NH₂, substituted or unsubstituted alkylamino groups,substituted or unsubstituted arylamino groups, substituted orunsubstituted dialkylamino groups, substituted or unsubstituteddiarylamino groups, substituted or unsubstituted (alkyl)(aryl)aminogroups, substituted or unsubstituted alkyl groups, substituted orunsubstituted aryl groups, —C(═O)H, —C(═O)-alkyl groups, or —C(═O)-arylgroups. One group of particularly preferred compounds of structure IIIare those in which R⁹ is hydrogen.

[0175] In compounds of structure III, R¹⁰ is selected from substitutedor unsubstituted alkyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups,—C(═O)-aryl groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups,—C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl)groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups,—N(alkyl)(aryl) groups, —N(aryl)₂ groups, —C(═O)NH(heterocyclyl) groups,—C(═O)N(heterocyclyl)₂ groups, —C(═O)N(alkyl)(heterocyclyl) groups, or—C(═O)N(aryl)(heterocyclyl) groups;

[0176] In compounds of structure III, R¹¹ and R¹⁹ may be the same ordifferent and are independently selected from substituted orunsubstituted alkyl groups, or substituted or unsubstituted aryl groupswhereas R¹² is selected from H, substituted or unsubstituted alkylgroups, substituted or unsubstituted aryl groups, or substituted orunsubstituted heterocyclyl groups.

[0177] In compounds of structure III, R¹³ is selected from H,substituted or unsubstituted alkyl groups, substituted or unsubstitutedaryl groups, substituted or unsubstituted heterocyclyl groups, —OH,alkoxy groups, aryloxy groups, —NH₂, substituted or unsubstitutedheterocyclylalkyl groups, substituted or unsubstituted aminoalkylgroups, substituted or unsubstituted alkylaminoalkyl groups, substitutedor unsubstituted dialkylaminoalkyl groups, substituted or unsubstitutedarylaminoalkyl groups, substituted or unsubstituted diarylaminoalkylgroups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted or unsubstituted alkylamino groups, substituted orunsubstituted arylamino groups, substituted or unsubstituteddialkylamino groups, substituted or unsubstituted diarylamino groups,substituted or unsubstituted (alkyl)(aryl)amino groups, —C(═O)H,—C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkyl groups,—C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl)groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)-N(heterocyclyl)₂ groups, —C(═O)-N(alkyl)(heterocyclyl) groups,—C(═O)-N(aryl)(heterocyclyl) groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkylgroups, substituted or unsubstituted alkoxyalkyl groups, substituted orunsubstituted aryloxyalkyl groups, or substituted or unsubstitutedheterocyclyloxyalkyl groups. R¹² and R¹³ may join together to form a 5to 7 membered saturated or unsaturated, substituted or unsubstitutedN-containing ring.

[0178] In compounds of structure III, R¹⁴ is selected from H, —OH,alkoxy groups, aryloxy groups, —NH₂, —NH(alkyl) groups, —NH(aryl)groups, —N(alkyl)₂ groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups,substituted or unsubstituted alkyl groups, substituted or unsubstitutedaryl groups, —NH(heterocyclyl) groups, —N(heterocyclyl)₂ groups,—N(alkyl)(heterocyclyl) groups, or —N(aryl)(heterocyclyl) groups.

[0179] In compounds of structure III, R¹⁵ is selected from substitutedor unsubstituted alkyl groups, substituted or unsubstituted aryl groups,substituted or unsubstituted heterocyclyl groups, substituted orunsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups,—C(═O)-aryl groups, —C(═O)-heterocyclyl groups, —C(═O)NH₂,—C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups,—C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups,—C(═O)NH-heterocyclyl groups, —C(═O)N—(heterocyclyl)₂ groups,—C(═O)N(alkyl)(heterocyclyl) groups, —C(═O)N(aryl)(heterocyclyl) groups,substituted or unsubstituted aminoalkyl groups, substituted orunsubstituted alkylaminoalkyl groups, substituted or unsubstituteddialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkylgroups, substituted or unsubstituted diarylaminoalkyl groups,substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substitutedor unsubstituted heterocyclylaminoalkyl groups, substituted orunsubstituted diheterocyclylaminoalkyl groups, substituted orunsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted orunsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted orunsubstituted alkoxyalkyl groups, substituted or unsubstitutedaryloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups,or substituted or unsubstituted heterocyclyloxyalkyl groups.

[0180] In compounds of structure III, R¹⁶ is selected from H,substituted or unsubstituted alkyl groups, substituted or unsubstitutedaryl groups, or substituted or unsubstituted heterocyclyl groups whereasR¹⁷ is selected from H, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, substituted or unsubstitutedheterocyclyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups,—C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl)groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted orunsubstituted aminoalkyl groups, substituted or unsubstitutedalkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkylgroups, substituted or unsubstituted arylaminoalkyl groups, substitutedor unsubstituted diarylaminoalkyl groups, substituted or unsubstituted(aryl)(alkyl)aminoalkyl groups, substituted or unsubstitutedheterocyclylalkyl groups, —C(═O)—heterocyclyl groups,—C(═O)—O—heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted or unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstitutedhydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups,substituted or unsubstituted aryloxyalkyl groups, or substituted orunsubstituted heterocyclyloxyalkyl groups. R¹⁶ and R¹⁷ may join togetherto form a 5 to 7 membered saturated or unsaturated, substituted orunsubstituted N-containing ring.

[0181] Finally, in compounds of structure III, R¹⁸, R²⁰, and R²¹ may bethe same or different and are independently selected H, —NH₂, —NH(alkyl)groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂ groups,—N(alkyl)(aryl) groups, —NH(heterocyclyl) groups,—N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups,—N(heterocyclyl)₂ groups, substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —OH, substituted orunsubstituted alkoxy groups, substituted or unsubstituted heterocyclylgroups, substituted or unsubstituted aryloxy groups, heterocyclyloxygroups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkylgroups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, or—N(aryl)O-aryl groups.

[0182] Preferred compounds having the structure III include those inwhich R¹⁸ is selected from substituted or unsubstituted alkyl groups,substituted or unsubstituted aryl groups, —NH₂, —NH(alkyl) groups,—N(alkyl)₂ groups, —NH(aryl) groups, —N(aryl)₂ groups, —N(alkyl)(aryl)groups, —NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups,—N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, or N-containingheterocycles, and the N-containing heterocycles are bonded to thecarbonyl carbon of the —C(═O)-R¹⁸ group through either a nitrogen atomor a carbon atom in the rings of the N-containing heterocycles. In stillmore preferred compounds in which R¹⁸ is a N-containing heterocycle, theN-containing heterocycle of the R¹⁸ group is selected from substitutedor unsubstituted morpholine, substituted or unsubstituted pyrrolidine,substituted or unsubstituted piperazine, substituted or unsubstitutedpiperidine, substituted or unsubstituted pyrrole, substituted orunsubstituted imidazole, substituted or unsubstituted pyrazole,substituted or unsubstituted 1,2,3-triazole, substituted orunsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole,substituted or unsubstituted thiomorpholine, substituted orunsubstituted homopiperazine, substituted or unsubstitutedoxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one,substituted or unsubstituted pyridine, substituted or unsubstitutedoxazole, substituted or unsubstituted isoxazole, substituted orunsubstituted thiazole, substituted or unsubstituted isothiazole,substituted or unsubstituted benzimidazole, substituted or unsubstitutedbenzoxazole, or substituted or unsubstituted benzothiazole.

[0183] Other preferred compounds having structure III are provided inwhich R¹⁵ or R¹⁷ is selected from substituted or unsubstitutedaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups,substituted or unsubstituted arylaminoalkyl groups, substituted orunsubstituted dialkylaminoalkyl groups, substituted or unsubstituteddiarylaminoalkyl groups, alkylarylaminoalkyl groups, or substituted orunsubstituted heterocycylalkyl groups, including: —CH₂(CH₂)_(p)NH₂groups, —CH₂(CH₂)_(p)NH(alkyl) groups, —CH₂(CH₂)_(p)NH(aryl) groups,—CH₂(CH₂)_(p)N(alkyl)₂ groups, —CH₂(CH₂)_(p)N(aryl)₂ groups,—CH₂(CH₂)_(p)N(alkyl)(aryl) groups, or —CH₂(CH₂)_(p)(heterocyclyl)groups, where p is an integer ranging from 0 to 4 and the heterocyclylgroup of the —CH₂(CH₂)_(p)(heterocyclyl) group is a N-containingheterocycle selected from substituted or unsubstituted morpholine,substituted or unsubstituted pyrrolidine, substituted or unsubstitutedpiperazine, substituted or unsubstituted piperidine, substituted orunsubstituted pyrrole, substituted or unsubstituted imidazole,substituted or unsubstituted pyrazole, substituted or unsubstituted1,2,3-triazole, substituted or unsubstituted 1,2,4-triazole, substitutedor unsubstituted tetrazole, substituted or unsubstituted thiomorpholine,substituted or unsubstituted homopiperazine, substituted orunsubstituted oxazolidin-2-one, substituted or unsubstitutedpyrrolidin-2-one, substituted or unsubstituted pyridine, substituted orunsubstituted oxazole, substituted or unsubstituted isoxazole,substituted or unsubstituted thiazole, substituted or unsubstitutedisothiazole, substituted or unsubstituted benzimidazole, substituted orunsubstituted benzoxazole, or substituted or unsubstitutedbenzothiazole.

[0184] Compounds of structure I and structure II may be synthesized fromsimple starting molecules as shown in Schemes 1-3 and exemplified in theExamples. As shown in Scheme 1, compounds of structure I and II maygenerally be prepared using pyridines or other heterocycles substitutedwith amines and carboxylic acid groups.

[0185] As shown in Scheme 1, a substituted pyridine such as asubstituted or unsubstituted 3-amino-pyridine-4-carboxylic acid may bereacted with an acyl halide such as methyl 2-(chlorocarbonyl)acetate toproduce an amide that will react with a substituted or unsubstituted1,2-diaminobenzene. The resulting product is a 4-hydroxy-substitutedcompound of structure I or II. The use of starting pyridines withdifferent substitution patterns such as 2-aminonicotinic acid(2-aminopyridine-4-carboxylic acid) provides compounds where thenitrogen is in a different position in the pyridine ring of the finalcompound. One skilled in the art will recognize that the procedure setforth in Scheme 1 may be modified to produce various compounds.

[0186] A method for preparing 4-amino substituted compounds ofstructures I and II is shown in Scheme 2.

[0187] As shown in Scheme 2, pyridines and other heterocyclessubstituted with amine and nitrile groups may be used to synthesize4-amino substituted compounds of Structure I and II. A compound such asethyl 2-cyanoacetate may be reacted with ethanol to produce ethyl3-ethoxy-3-iminopropanoate hydrochloride. Subsequent reaction with asubstituted or unsubstituted 1,2-phenylenediamine provides substitutedor unsubstituted ethyl 2-benzimidazol-2-ylacetate. Reaction of asubstituted or unsubstituted ethyl 3 benzimidazol-2-ylacetate with apyridine having an amine and nitrile group such as substituted orunsubstituted 3-amino-4-cyanopyridine with a base such as lithiumbis(trimethylsilyl)amide or a Lewis acid such as tin tetrachlorideprovides the substituted or unsubstituted 4-amino substituted compoundof structure I and II.

[0188] Scheme 3 illustrates a general synthetic route that allows forthe synthesis of 4-dialkylamino and 4-alkylamino compounds of structuresI and II. An inspection of Scheme 3 shows that 4-hydroxy substitutedcompounds of structure I or II may be converted into the 4-chloroderivative by reaction with phosphorous oxychloride. The 4-chloroderivative may then be reacted with an alkylamine or dialkylamine toproduce the corresponding 4-alkylamino or 4-dialkylamino derivative.Deprotection affords the final 4-alkylamino or 4-dialkylamino compoundsof structure I and II. Other groups that may be reacted with the4-chloro derivative in this manner include, but are not limited to, ROH,RSH, and CuCN.

[0189] Heteroaromatic diamines may be used as precursors of compounds ofstructure III. The synthesis of compounds of structure III where Y=NH₂is depicted in Scheme 4.

[0190] A compound such as ethyl cyanoacetate may be condensed with asubstituted or unsubstituted heterocycle containing two ortho aminogroups such as a substituted or unsubstituted 1,2-diaminopyridine toobtain a substituted or unsubstituted2-imidazolo[5,4-b]pyridin-2-ylethanenitrile, which may be hydrolyzed inacidic medium to provide a substituted or unsubstituted ethyl2-imidazolo[5,4-b]pyridin-2-ylacetate. As an alternate route, asubstituted or unsubstituted ethyl 2-imidazolo[5,4-b]pyridin-2-ylacetatemay be obtained from a compound such as the hydrochloride salt of3-ethoxy-3-iminopropanoate and a substituted or unsubtituted1,2-diaminopyridine. Reaction of a substituted or unsubstituted ethyl2-imidazolo[5,4-b]pyridin-2-ylacetates with a pyridine having an amineand nitrile group such as a substituted or unsubstituted3-amino-4-cyanopyridine and a base such as lithiumbis(trimethylsilyl)amide provides the substituted or unsubstitutedcompound of structure III.

[0191] Scheme 5 illustrates just a few of the methods that may be usedto produce a variety of 2-amino anilines. Halo (X=halogen) nitroanilinesmay be reacted with a wide variety of nucleophiles (Nu⁻) such asalcohols and amines to produce functionalized nitroanilines which maysubsequently be reduced to diamines. The alcohol moiety of a nitroaminophenol may be modified using known methods to introduce a broad range ofsubstituents into a diamine for subsequent inclusion in compound of theinvention.

[0192] The instant invention also provides for compositions which may beprepared by mixing one or more compounds of the instant invention, orpharmaceutically acceptable salts or tautomers thereof, withpharmaceutically acceptable carriers, excipients, binders, diluents orthe like to treat or ameliorate a variety of disorders related to theactivity of VEGF-RTK, more particularly angiogenesis associated withcancer. Such compositions can be in the form of, for example, granules,powders, tablets, capsules, syrup, suppositories, injections, emulsions,elixirs, suspensions or solutions. The instant compositions can beformulated for various routes of administration, for example, by oraladministration, by nasal administration, by rectal administration,subcutaneous injection, intravenous injection, intramuscular injections,or intraperitoneal injection. The following dosage forms are given byway of example and should not be construed as limiting the instantinvention.

[0193] For oral, buccal, and sublingual administration, powders,suspensions, granules, tablets, pills, capsules, gelcaps, and capletsare acceptable as solid dosage forms. These can be prepared, forexample, by mixing one or more compounds of the instant invention, orpharmaceutically acceptable salts or tautomers thereof, with at leastone additive such as a starch or other additive. Suitable additives aresucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch,agar, alginates, chitins, chitosans, pectins, tragacanth gum, gumarabic, gelatins, collagens, casein, albumin, synthetic orsemi-synthetic polymers or glycerides. Optionally, oral dosage forms cancontain other ingredients to aid in administration, such as an inactivediluent, or lubricants such as magnesium stearate, or preservatives suchas paraben or sorbic acid, or anti-oxidants such as ascorbic acid,tocopherol or cysteine, a disintegrating agent, binders, thickeners,buffers, sweeteners, flavoring agents or perfuming agents. Tablets andpills may be further treated with suitable coating materials known inthe art.

[0194] Liquid dosage forms for oral administration may be in the form ofpharmaceutically acceptable emulsions, syrups, elixirs, suspensions, andsolutions, which may contain an inactive diluent, such as water.Pharmaceutical formulations may be prepared as liquid suspensions orsolutions using a sterile liquid, such as, but not limited to, an oil,water, an alcohol, and combinations of these. Pharmaceutically suitablesurfactants, suspending agents, emulsifying agents, may be added fororal or parenteral administration.

[0195] As noted above, suspensions may include oils. Such oil include,but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oiland olive oil. Suspension preparation may also contain esters of fattyacids such as ethyl oleate, isopropyl myristate, fatty acid glyceridesand acetylated fatty acid glycerides. Suspension formulations mayinclude alcohols, such as, but not limited to, ethanol, isopropylalcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, suchas but not limited to, poly(ethyleneglycol), petroleum hydrocarbons suchas mineral oil and petrolatum; and water may also be used in suspensionformulations.

[0196] For nasal administration, the pharmaceutical formulations may bea spray or aerosol containing and appropriate solvents and optionallyother compounds such as, but not limited to, stabilizers, antimicrobialagents, antioxidants, pH modifiers, surfactants, bioavailabilitymodifiers and combinations of these. A propellant for an aerosolformulation may include compressed air, nitrogen, carbon dioxide, or ahydrocarbon based low boiling solvent.

[0197] Injectable dosage forms generally include aqueous suspensions oroil suspensions which may be prepared using a suitable dispersant orwetting agent and a suspending agent. Injectable forms may be insolution phase or in the form of a suspension, which is prepared with asolvent or diluent. Acceptable solvents or vehicles include sterilizedwater, Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils may be employed as solvents or suspendingagents. Preferably, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

[0198] For injection, the pharmaceutical formulation may be a powdersuitable for reconstitution with an appropriate solution as describedabove. Examples of these include, but are not limited to, freeze dried,rotary dried or spray dried powders, amorphous powders, granules,precipitates, or particulates. For injection, the formulations mayoptionally contain stabilizers, pH modifiers, surfactants,bioavailability modifiers and combinations of these.

[0199] For rectal administration, the pharmaceutical formulations may bein the form of a suppository, an ointment, an enema, a tablet or a creamfor release of compound in the intestines, sigmoid flexure and/orrectum. Rectal suppositories are prepared by mixing one or morecompounds of the instant invention, or pharmaceutically acceptable saltsor tautomers of the compound, with acceptable vehicles, for example,cocoa butter or polyethylene glycol, which is present in a solid phaseat normal storing temperatures, and present in a liquid phase at thosetemperatures suitable to release a drug inside the body, such as in therectum. Oils may also be employed in the preparation of formulations ofthe soft gelatin type and suppositories. Water, saline, aqueous dextroseand related sugar solutions, and glycerols may be employed in thepreparation of suspension formulations which may also contain suspendingagents such as pectins, carbomers, methyl cellulose, hydroxypropylcellulose or carboxymethyl cellulose, as well as buffers andpreservatives.

[0200] Besides those representative dosage forms described above,pharmaceutically acceptable excipients and carries are generally knownto those skilled in the art and are thus included in the instantinvention. Such excipients and carriers are described, for example, in“Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991),which is incorporated herein by reference.

[0201] The formulations of the invention may be designed for to beshort-acting, fast-releasing, long-acting, and sustained-releasing asdescribed below. Thus, the pharmaceutical formulations may also beformulated for controlled release or for slow release.

[0202] The instant compositions may also comprise, for example, micellesor liposomes, or some other encapsulated form, or may be administered inan extended release form to provide a prolonged storage and/or deliveryeffect. Therefore, the pharmaceutical formulations may be compressedinto pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections or as implants such as stents. Suchimplants may employ known inert materials such as silicones andbiodegradable polymers.

[0203] Specific dosages may be adjusted depending on conditions ofdisease, the age, body weight, general health conditions, sex, and dietof the subject, dose intervals, administration routes, excretion rate,and combinations of drugs. Any of the above dosage forms containingeffective amounts are well within the bounds of routine experimentationand therefore, well within the scope of the instant invention.

[0204] A therapeutically effective dose may vary depending upon theroute of administration and dosage form. The preferred compound orcompounds of the instant invention is a formulation that exhibits a hightherapeutic index. The therapeutic index is the dose ratio between toxicand therapeutic effects which can be expressed as the ratio between LD₅₀and ED₅₀. The LD₅₀ is the dose lethal to 50% of the population and theED₅₀ is the dose therapeutically effective in 50% of the population. TheLD₅₀ and ED₅₀ are determined by standard pharmaceutical procedures inanimal cell cultures or experimental animals.

[0205] “Treating” within the context of the instant invention, means analleviation of symptoms associated with a disorder or disease, or haltof further progression or worsening of those symptoms, or prevention orprophylaxis of the disease or disorder. For example, within the contextof treating patients in need of an inhibitor of VEGF-RTK, successfultreatment may include a reduction in the proliferation of capillariesfeeding a tumor or diseased tissue, an alleviation of symptoms relatedto a cancerous growth or tumor, proliferation of capillaries, ordiseased tissue, a halting in capillary proliferation, or a halting inthe progression of a disease such as cancer or in the growth ofcancerous cells. Treatment may also include administering thepharmaceutical formulations of the present invention in combination withother therapies. For example, the compounds and pharmaceuticalformulations of the present invention may be administered before,during, or after surgical procedure and/or radiation therapy. Thecompounds of the invention can also be administered in conjunction withother anti-cancer drugs including those used in antisense and genetherapy. Examples of standard chemotherapeutic agents that the compoundsof the present may be used with include, but are not limited to,cisplatin, taxol, and 5-fluorouracil.

[0206] Pharmaceutical formulations according to the invention includeany of the compounds described above in combination with apharmaceutically acceptable carrier.

[0207] A method of treating a patient in need of an inhibitor ofvascular endothelial growth factor receptor tyrosine kinase includesadministering an effective amount of a pharmaceutical formulationaccording to the invention to a patient in need thereof.

[0208] A method for inhibiting tumor growth in a patient includesadministering an effective amount of the compound or a pharmaceuticallyacceptable salt thereof to a patient having a tumor.

[0209] A method for inhibiting the proliferation of capillaries in apatient includes administering an effective amount of the compound or apharmaceutically acceptable salt thereof according to a patient in need.

[0210] A method of preparing pharmaceutical formulations includes mixingany of the above-described compounds with a pharmaceutically acceptablecarrier and water or an aqueous solution.

[0211] The present invention, thus generally described, will beunderstood more readily by reference to the following examples, whichare provided by way of illustration and are not intended to be limitingof the present invention.

EXAMPLES

[0212] The following abbreviations are used throughout the Examples:ATP: Adenosine triphosphate BSA: Bovine Serum Albumin DMSO:Dimethylsulfoxide DTT: DL-Dithiothreitol EDTA: Ethylene diaminetetraacetic acid EtOAc: Ethyl acetate EtOH: Ethanol HBTU:O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphateIC₅₀ value: The concentration of an inhibitor that causes a 50 percentreduction in a measured activity LiHMDS: Lithiumbis(trimethylsilyl)amide MeOH: Methanol NaOH: Sodium hydroxide NaOMe:Sodium methoxide NMP: N-methylpyrrolidone TFA: Trifluoroacetic acid THF:Tetrahydrofuran

[0213] Various functionalized aryl diamines were obtained fromcommercial sources, prepared by methods know to those of skilled in theart, or were prepared by the following general methods. The compoundswere named using Nomenclator (v. 3.0 & v. 5.0) from CmemInovationSoftware, Inc. and ACD/Name v. 4.53.

[0214] The various aryl diamine starting materials used to synthesizebenzimidazole acetates may be obtained from commercial sources, preparedby methods know to one of skill in the art, or prepared by the followinggeneral methods 1-7.

[0215] 2,4-Difluoronitrobenzene (1.0 eq) was placed in a dryround-bottomed flask equipped with a dry ice condenser charged withacetone and dry ice. Ammonia was condensed into the flask and theresulting solution was stirred at reflux for 7 hours. A yellowprecipitate formed within 1 hour. After 7 hours, the condenser wasremoved and the liquid ammonia was allowed to evaporate over severalhours. The crude product was purified by flash chromatography on silicagel (85:15 hexanes:ethyl acetate, product at R_(f)=0.32, contaminant atR_(f)=0.51); GC/MS m/z 156.1 (M+), R_(t) 11.16 minutes.

[0216] The resulting 5-fluoro-2-nitrophenylamine (1.0 eq) and an amine(1.1 eq) e.g. N-methyl piperazine, were dissolved in NMP andtriethylamine (2.0 eq) was added. The reaction mixture was heated at100° C. for 3 hours. The solution was then cooled to room temperatureand diluted with water. The resulting precipitate was filtered and driedunder vacuum to provide the 2-nitro-diamino product. Alternatively, thesame product may be obtained from commercially available5-chloro-2-nitrophenylamine under identical conditions except heating at130° C. for 1-2 days. In some examples, the displacement on either5-fluoro-2-nitrophenylamine or 5-chloro-2-nitrophenylamine can beconducted in neat amine (5 eq) at 100° C. or 130° C., respectively. Theproduct is isolated in an identical manner. LC/MS m/z 237.1 (MH+), R_(t)1.304 minutes.

[0217] The nitroamine (1.0 eq) and 10% Pd/C (0.1 eq) was suspended inanhydrous ethanol at room temperature. The reaction flask was evacuatedand subsequently filled with H₂. The resulting mixture was then stirredunder a hydrogen atmosphere overnight. The resulting solution wasfiltered through Celite and concentrated under vacuum to provide thecrude product which was used without further purification.

[0218] A round-bottom flask was charged with2,3-difluoro-6-nitrophenylamine (1 eq) and enough NMP to make a viscousslurry. An amine (5 eq), e.g. N-methyl piperazine, was added and thesolution was heated at 100° C. After 2 hours, the solution was cooledand poured into water. A bright yellow solid formed which was filteredand dried. The nitroamine was reduced as in Method 1 to provide thecrude product which was used without further purification. LC/MS m/z225.1 (MH+), R_(t)0.335 minutes.

[0219] To a 0.1 M DMF solution of 1,3-difluoro-2-nitrobenzene was addedEt3N (2 eq) followed by an amine (1 eq), e.g. morpholine. The mixturewas stirred for 18 hours and then diluted with water and extracted withethyl acetate. LC/MS m/z 227.2 (MH+), R_(t)2.522 minutes. The combinedorganic layers were dried over MgSO₄, filtered, and concentrated.Ammonia was condensed into a bomb containing the crude product. The bombwas sealed and heated to 100° C. (over 400 psi). After 72 hours the bombwas allowed to cool and the ammonia was evaporated to provide a reddishsolid. The nitroamine was reduced as in Method 1 to provide the crudeproduct which was used without further purification. LC/MS m/z 194.1(MH+), R_(t) 1.199 minutes.

[0220] To a stirred NMP solution containing NaH (1.3 eq) was added analcohol (1.0 eq), e.g. 2-methyloxyethanol. The resulting mixture wasthen stirred for 30 minutes. A slurry of 5-fluoro-2-nitrophenylamine inNMP was then added slowly. The mixture was then heated to 100° C. After2 hours, the reaction mixture was cooled and water was added. Themixture was then filtered and the captured solid was washed with waterand purified by silica gel chromatography (1:1 ethyl acetate:hexane).LC/MS m/z 213.2 (MH+), R_(t)2.24 minutes. The nitroamine was reduced asin Method 1 to provide the crude product which was used without furtherpurification. LC/MS m/z 183.1 (MH+), R_(t)0.984 minutes.

[0221] Diisopropyl azodicarboxylate (1.1 eq) was added dropwise to astirred solution of 4-amino-3-nitrophenol (1.0 eq), triphenylphosphine(1.1 eq), and an alcohol, e.g. N-(2-hydroxyethyl)morpholine (1.0 eq), intetrahydrofuran at 0° C. The mixture was allowed to warm to roomtemperature and stirred for 18 hours. The solvent was evaporated, andthe product was purified by silica gel chromatography (98:2CH₂Cl₂:methanol) to yield 4-(2-morpholin-4-ylethoxy)-2-nitrophenylamineas a dark reddish-brown oil. LC/MS m/z 268.0 (MH+), R_(t) 1.01 minutes.The nitroamine was reduced as in Method 1 to give the crude productwhich was used without further purification. LC/MS m/z 238.3 (MH+),R_(t) 0.295 minutes.

[0222] To a flask charged with 4-amino-3-nitrophenol (1 eq), K₂CO₃ (2eq), and 2-butanone was added an alkyl dibromide, e.g.1,3-dibromopropane (1.5 eq). The resulting mixture was then heated at80° C. for 18 hours. After cooling, the mixture was filtered,concentrated, and diluted with water. The solution was then extractedwith CH₂Cl₂ (3×) and the combined organic layers were concentrated togive a solid that was then washed with pentane. LCMS m/z 275.1 (MH+),R_(t)2.74 minutes.

[0223] An acetonitrile solution of the bromide prepared above, an amine,e.g. pyrrolidine (5 eq), CS₂CO₃ (2 eq) and Bu4NI (0.1 eq) was heated at70° C. for 48 hours. The reaction mixture was cooled, filtered, andconcentrated. The residue was dissolved in CH₂Cl₂, washed with water,and concentrated to give the desired nitroamine,2-nitro-4-(3-pyrrolidin-1-ylpropoxy)phenylamine. LCMS m/z 266.2 (MH+),R_(t) 1.51 minutes. The nitroamine was reduced as in Method 1 to providethe crude product which was used without further purification.

[0224] To a suspension of 6-chloro-3-nitropyridin-2-amine (1 eq) inacetonitrile was added an amine, e.g. morpholine (4 eq). The resultingreaction mixture was stirred at 70° C. for 5 hours. The solvent wasevaporated under reduced pressure, and the residue triturated with etherto provide the desired compound as a bright yellow powder. LC/MS m/z225.0 (MH+), R_(t) 1.79 minutes. The nitroamine was reduced as in Method1 to provide the crude product which was used without furtherpurification.

Example 1 3-[2-(Methoxycarbonyl)acetylamino]pyridine-4-carboxylic acid

[0225] A solution of 3-aminopyridine-4-carboxylic acid (1.0 eq), methyl2-(chlorocarbonyl)acetate (1.1 eq), and triethylamine (2.0 eq) inacetone was stirred overnight at room temperature. The solvent wasremoved in vacuo. The product was used without further purification.LC/MS m/z 239.2 (MH+), R_(t) 1.40 minutes.

3-Benzimidazol-2-yl-4-hydroxyhydropyridino[3,4-b]pyridin-2-one

[0226] 3-[2-(Methoxycarbonyl)acetylamino]pyridine-4-carboxylic acid (1.1eq) was combined with 1,2-phenylenediamine (1.0 eq) and heated at 150°C. for 3 hours. The crude product was purified by reversed-phase HPLC(DMSO/5% TFA). LC/MS m/z 279.3 (MH+), R_(t) 1.73 minutes.

Example 24-Hydroxy-3-(5-methylbenzimidazol-2-yl)hydropyridino[3,4-b]pyridin-2-one

[0227] The title compound was synthesized as described in Example 1using 3-[2-(methoxycarbonyl)acetylamino]-pyridine-4-carboxylic acid and4-methyl-1,2-phenylenediamine. The crude product was purified byreversed-phase HPLC (DMSO/5% TFA). LC/MS m/z 293.3 (MH+), R_(t) 1.99minutes.

Example 3 Ethyl 2-benzimidazol-2-ylacetate

[0228] A solution of 1,2-phenylenediamine (1.0 eq) and ethyl3-ethoxy-3-iminopropanoate hydrochloride (1.3 eq) in EtOH was stirred at90° C. overnight. The reaction was cooled to room temperature and thesolvent removed in vacuo. Water and CH₂Cl₂ were added to the residue.The organic layer was separated, dried over Na₂SO₄ and the solventremoved. The solid recovered was used without purification. LC/MS m/z205.2 (MH+), R_(t) 1.44 minutes.

Method A 2-Benzimidazol-2-yl-N-(4-cyano(3-pyridyl))acetamide

[0229] LiHMDS (2.5 eq) was added to ethyl 2-benzimidazol-2-ylacetate(1.0 eq) in THF at −78° C. After 1 hour, 3-amino-4-cyanopyridine (0.8eq) in THF was added. The resulting mixture was allowed to warm to roomtemperature overnight. The mixture was quenched with NH₄Cl (aqueoussaturated solution) and extracted with EtOAc. The organic layer washedwith H₂O and brine, dried over Na₂SO₄, filtered, and concentrated invacuo to yield a brown solid. The crude material was purified by silicagel chromatography (5:1 EtOAc:hexane) to yield the desired product.LC/MS m/z 278.3 (MH+), R_(t) 1.88 minutes.

4-Amino-3-benzimidazol-2-ylhydropyridino[3,4-b]pyridin-2-one

[0230] 2-Benzimidazol-2-yl-N-(4-cyano(3-pyridyl))acetamide (1.0 eq) washeated in NaOMe (18 eq, 0.5 M in MeOH) at 70° C. for 2 hours. Thereaction mixture was cooled, and the resulting solid was filtered andwashed with water to provide the desired product. LC/MS m/z 278.3 (MH+),R_(t) 1.91 minutes.

Example 4 Ethyl 2-(5-methylbenzimidazol-2-yl)acetate

[0231] The title compound was synthesized as described in Example 3using 4-methyl-1,2-phenylenediamine. LC/MS m/z 219.3 (MH+), R_(t) 1.60minutes.

N-(4-Cyano(3-pyridyl))-2-(5-methylbenzimidazol-2-yl)acetamide

[0232] The title compound was synthesized as described in Example 3,Method A using ethyl 2-(5-methylbenzimidazol-2-yl)acetate. LC/MS m/z292.4 (MH+), R_(t) 1.71 minutes.

4-Amino-3-(5-methylbenzimidazol-2-yl)hydropyridino[3,4-b]pyridin-2-one

[0233] The title compound was synthesized as described in Example 3,Method A usingN-(4-cyano(3-pyridyl))-2-(5-methylbenzimidazol-2-yl)acetamide. LC/MS m/z292.4 (MH+), R_(t) 2.04 minutes.

Example 5 4-(2-Morpholin-4-ylethoxy)-2-nitrophenylamine

[0234] Diisopropyl azodicarboxylate (1.1 eq) was added dropwise to astirred solution of 4-amino-3-nitrophenol (1.0 eq), triphenylphosphine(1.1 eq), and N-(2-hydroxyethyl)morpholine (1.0 eq), in THF at 0° C. Themixture was allowed to warm to room temperature and left to stir for 18hours. The solvent was evaporated and the product was purified by silicagel chromatography (98:2 CH₂Cl₂:MeOH) to yield a dark reddish-brown oil.LC/MS m/z 268.0 (MH+), R_(t) 1.01 minutes.

4-(2-Morpholin-4-ylethoxy)benzene-1,2-diamine

[0235] To a solution 4-(2-morpholin-4-ylethoxy)-2-nitrophenylamine (1.0eq) in EtOH was added Pd/C (0.1 eq). The reaction vessel was repeatedlypurged with nitrogen, then stirred under a hydrogen atmosphere (1 atm)for 18 hours. The product was filtered through a Celite plug, and theplug washed with EtOH. The diamine was used without purification. LC/MSm/z 238.3 (MH+), R_(t) 0.295 minutes.

Ethyl 2-[5-(2-morpholin-4-ylethoxy)benzimidazol-2-yl]acetate

[0236] The title compound was synthesized as described in Example 3using 4-(2-morpholin-4-ylethoxy)benzene-1,2-diamine. The organic layerwas concentrated and the residue purified by silica gel chromatography(10:1:2 CH₂Cl₂:MeOH:EtOAc) to yield a dark reddish brown oil. LC/MS m/z334.4 (MH+), R_(t) 1.08 minutes.

N-(4-Cyano(3-pyridyl))-2-[5-(2-morpholin-4-ylethoxy)benzimidazol-2-yl]acetamide

[0237] The title compound was synthesized as described in Example 3,Method A using ethyl2-[5-(2-morpholin-4-ylethoxy)benzimidazol-2-yl]acetate. LC/MS m/z 407.4(MH+), R_(t) 1.25 minutes.

4-Amino-3-[5-(2-morpholin-4-ylethoxy)benzimidazol-2-yl]hydropyridino[3,4-b]pyridin-2-one

[0238] The title compound was synthesized as described in Example 3,Method A usingN-(4-cyano(3-pyridyl))-2-[5-(2-morpholin-4-ylethoxy)benzimidazol-2-yl]acetamide.LC/MS m/z 407.4 (MH+), R_(t) 1.41 minutes.

Example 6 2-[(Ethoxycarbonyl)methyl]benzimidazole-5-carboxylic acid

[0239] The title compound was synthesized as described in Example 3using 3,4-diaminobenzoic acid. The crude material was purified by silicagel chromatography (0-5% MeOH/CH₂Cl₂) to afford the desired product as awhite to off-white solid. LC/MS m/z 249.1 (MH+), R_(t) 1.35 minutes.

Ethyl 2-[5-(N,N-dimethylcarbamoyl)benzimidazol-2-yl]acetate

[0240] 2-[(Ethoxycarbonyl)methyl]benzimidazole-5-carboxylic acid (1.0eq) was dissolved in THF. HBTU (1.1 eq) and diisopropylethylamine (2.0eq) were added, followed by dimethylamine (2.0 M in THF, 1.1 eq). Thereaction was stirred at room temperature overnight then concentrated andthe residue was purified by silica gel chromatography (5:95 MeOH/CH₂Cl₂)to afford the desired compound. LC/MS m/z 276.2 (MH+), R_(t) 1.18minutes.

Method B[2-(4-Amino-2-oxohydropyridino[3,4-b]pyridin-3-yl)benzimidazol-5-yl]-N,N-dimethylcarboxamide

[0241] Ethyl 2-[5-(N,N-dimethylcarbamoyl)benzimidazol-2-yl]acetate (1.0eq) and anthranilonitrile (1.0 eq) were dissolved in 1,2-dichloroethane,and then SnCl₄ (5.5 eq) was added. The mixture was heated at refluxovernight. Upon cooling, the mixture was concentrated in vacuo. NaOH (3M) was added to the solid, and the mixture heated at 80° C. for 0.5hours. The solid was filtered and washed sequentially with H₂, CH₂Cl₂,and acetone. LC/MS indicated that the product was present in the acetonelayer and the solid. These fractions were combined and purified bysilica gel chromatography (5-10% MeOH in CH₂Cl₂ with 1% Et₃N) to givethe desired product. LC/MS m/z 349.3 (MH+), R_(t) 1.68 minutes.

Example 7 5-Fluoro-2-nitrophenylamine

[0242] 2,4-Difluoronitrobenzene (1.0 eq) was placed in a dryround-bottomed flask equipped with a dry ice condenser charged withacetone/dry ice. Ammonia was condensed into the flask and the resultingsolution was stirred at reflux for 7 hours. A yellow precipitate wasformed within 1 hour. After 7 hours, the condenser was removed and theliquid ammonia was allowed to evaporate over several hours. The crudeproduct was purified by flash chromatography on silica gel (85:15hexanes:EtOAc, product at R_(f)=0.32, contaminant at R_(f)=0.51). GC/MSm/z 156.1 (M+), R_(t) 11.16 minutes.

5-Morpholin-4-yl-2-nitrophenylamine

[0243] 5-Fluoro-2-nitrophenylamine (1.0 eq) and morpholine (3.0 eq) weredissolved in NMP and heated at 100° C. for 1 hour. The solution wascooled to room temperature and diluted with water. The resultingprecipitate was filtered and dried under vacuum to yield5-morpholin-4-yl-2-nitrophenylamine. The resulting solid wasrecrystallized from EtOH to afford pure product as a bright yellowsolid. LC/MS m/z 224.1 (MH+), R_(t) 1.89 minutes.

Ethyl 2-(5-morpholin-4-ylbenzimidazol-2-yl)acetate

[0244] The title compound was synthesized as described in Example 5using 5-morpholin-4-yl-2-nitrophenylamine. The crude yellow oil waspurified by flash column chromatography (89.5:10:0.5 CH₂Cl₂:MeOH:Et₃N)to yield pure product as a yellow solid. LC/MS m/z 290.3 (MH+), R_(t)1.31 minutes.

4-Amino-3-(5-morpholin-4-ylbenzimidazol-2-yl)hydropyridino[3,4-b]pyridin-2-one

[0245] The title compound was synthesized as described in Example 6,Method B using ethyl 2-(5-morpholin-4-ylbenzimidazol-2-yl)acetate. LC/MSm/z 363.2 (MH+), R_(t) 1.60 minutes.

Example 8 [1-(3-Amino-4-nitrophenyl)pyrrolidin-3-yl]dimethylamine

[0246] The title compound was synthesized as described in Example 7using 3-(dimethylamino)pyrrolidine. LC/MS m/z 251.3 (MH+), R_(t) 1.25minutes.

Ethyl 2-{5-[3-(dimethylamino)pyrrolidinyl]benzimidazol-2-yl}acetate

[0247] The title compound was synthesized as described in Example 5using [1-(3-amino-4-nitrophenyl)pyrrolidin-3-yl]dimethylamine and theresulting diamine was used according to Example 3 to form thebenzimidazole. The product was obtained as a yellow oil. LC/MS m/z 317.4(MH+), R_(t) 1.36 minutes.

4-Amino-3-{5-[3-(dimethylamino)pyrrolidinyl]benzimidazol-2-yl}hydropyridino[3,4-b]pyridin-2-one

[0248] The title compound was synthesized as described in Example 6,Method B using ethyl 2-[5-(dimethylamino)benzimidazol-2-yl]acetate.LC/MS m/z 390.2 (MH+), R_(t) 1.45 minutes.

Example 9 3H-Imidazo[4,5-b]pyridin-2-ylacetonitrile

[0249] Ethyl cyanoacetate (1.5 eq) and 2,3-diaminopyridine (1 eq) wereheated at 185° C. for 30 minutes. The reaction mixture was cooled toroom temperature and the black solid was triturated with ether. Thedesired product was thus obtained as a dark brown powder. LC/MS m/z159.1 (MH+), R_(t)0.44 minutes.

Ethyl 3H-imidazo[4,5-b]pyridin-2-ylacetate

[0250] 3H-Imidazo[4,5-b]pyridin-2-ylacetonitrile was suspended in EtOH,and gaseous HCl was bubbled through for 3 hours. The suspensioninitially dissolved, but a precipitate started forming almostimmediately. The reaction mixture was cooled to 0° C. and a coldsaturated NaHCO₃ solution was carefully added. Solid NaHCO₃ was alsoadded until a pH of 7.6 was achieved. The aqueous phase was thenextracted with EtOAc, and the organic extracts were dried (Na₂SO₄).After evaporation of the solvent under reduced pressure, the residue waspurified by chromatography on silica gel (10% MeOH in CH₂Cl₂ with 1%Et₃N) providing the desired product as a light brown solid. LC/MS m/z206.1 (MH+), R_(t)0.97 minutes.

4-Amino-3-(3H-imidazo[4,5-b]pyridin-2-yl)-1,7-naphthyridin-2(1H)-one

[0251] LiHMDS (3.0 eq) was added to ethyl3H-imidazo[4,5-b]pyridin-2-ylacetate (1.0 eq) in THF at −78° C. After 20minutes, a solution of 3-aminopyridine-4-carbonitrile (1.1 eq) in THFwas added. The resulting mixture was allowed to warm to roomtemperature, stirred 3 hours, and then refluxed overnight. The mixturewas cooled to 0° C. and quenched with an aqueous saturated NH₄Clsolution. A precipitate formed, was filtered off, and was washedrepeatedly with ether to yield the desired compound as a brown solid.Purification by reverse phase chromatography afforded the desiredproduct as a yellow solid. LC/MS m/z 279.0 (MH+), R_(t) 1.29 minutes.

Example 104-Amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1,7-naphthyridin-2(1H)-one

[0252] LiHMDS (3.6 eq) was added to ethyl[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]acetate (1.0 eq) and3-aminopyridine-4-carbonitrile (1.0 eq) in THF at 0° C. The reaction wasstirred overnight. The resulting mixture was quenched with an aqueoussaturated NH₄Cl solution and extracted with EtOAc. The combined organiclayers were washed with H₂O and brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo to yield a green solid. The crude material waswashed successively with CH₂Cl₂ and MeOH and then was purified byreverse phase HPLC to provide the desired product. LC/MS m/z 376.3(MH+), R_(t) 1.70 minutes.

Example 114-Amino-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-1,6-naphthyridin-2(1H)-one

[0253] LiHMDS (3.3 eq) was added to ethyl(5-morpholin-4-yl-1H-benzimidazol-2-yl)acetate (1.0 eq) and4-aminopyridine-3-carbonitrile (see J. Chem. Soc. 1967, p1558-1564; 1.0eq) in THF at 0° C. The reaction was stirred overnight. The resultingmixture was quenched with an aqueous saturated NH₄Cl solution andextracted with EtOAc. The combined organic layers were washed with H₂Oand brine, dried over Na₂SO₄, filtered, and concentrated in vacuo toyield a brown solid. The crude material was washed successively withCH₂Cl₂ and MeOH, and then was purified by reverse phase HPLC to providethe desired product. LC/MS m/z 363.2 (MH+), R_(t) 1.55 minutes.

Example 124-Amino-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-1H-benzimidazol-2-yl}-1,5-naphthyridin-2(1H)-one

[0254] LiHMDS (3.6 eq) was added to ethyl{5-[3-(dimethylamino)pyrrolidin-1-yl]-1H-benzimidazol-2-yl}acetate (1.0eq) and 3-aminopyridine-2-carbonitrile (J. Org. Chem. 1958, 1616-1617;1.0 eq) in THF at 0° C. The reaction was stirred overnight and thenheated at 40° C. for 3 hours. The resulting mixture was quenched with anaqueous saturated NH₄Cl solution and extracted with EtOAc. The combinedorganic layers were washed with H₂O and brine, dried over Na₂SO₄,filtered, and concentrated in vacuo to yield a green solid. The crudematerial was washed successively with CH₂Cl₂ and MeOH, and then waspurified by reverse phase HPLC to provide the desired product. LC/MS m/z390.2 (MH+), R_(t) 1.79 minutes.

Example 134-Amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1,5-naphthyridin-2(1H)-one

[0255] LiHMDS (3.6 eq) was added to ethyl[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]acetate (1.0 eq) and3-aminopyridine-2-carbonitrile (1.0 eq) in THF at 0° C. The reaction wasstirred overnight and then heated at 40° C. for 3 hours. The resultingmixture was quenched with an aqueous saturated NH₄Cl solution andextracted with EtOAc. The combined organic layers were washed with H₂Oand brine, dried over Na₂SO₄, filtered, and concentrated in vacuo toyield a green solid. The crude material was washed successively withCH₂Cl₂ and MeOH, and then was purified by reverse phase HPLC to providethe desired product. LC/MS m/z 376.1 (MH+), R_(t) 1.50 minutes.

Example 14 3-(1H-Benzimidazol-2-yl)-4-hydroxy-1,8-naphthyridin-2(1H)-one

[0256] The synthesis of the title compound is outlined in Scheme 5.

Example 15 2-(1H-Benzimidazol-2-yl)-N-(4-cyano-1H-pyrazol-5-yl)acetamide

[0257] LiHMDS (4.3 eq) was added to ethyl 1H-benzimidazol-2-ylacetate(1.0 eq) 5-amino-1H-pyrazole-4-carbonitrile (1.0 eq) in THF at 0° C.After 1 hour, the resulting mixture was warmed to room temperature,stirred overnight, and then heated at 40° C. for 4 hours. The mixturewas quenched with an aqueous saturated NH₄Cl solution and extracted withEtOAc. The organic layer was washed with H₂O and brine, dried overNa₂SO₄, filtered, and concentrated in vacuo to yield a tan solid. LC/MSm/z 267.1 (MH+), R_(t) 1.37 minutes.

4-Amino-5-(1H-benzimidazol-2-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0258] 2-(1H-Benzimidazol-2-yl)-N-(4-cyano-1H-pyrazol-5-yl)acetamide(1.0 eq) was heated in NaOMe (20 eq, 0.5 M in MeOH) at 100° C. for 2days. H₂O was added, and the mixture was extracted with EtOAc. Theorganic layer was washed with H₂O and brine, dried over Na₂SO₄,filtered, and concentrated in vacuo to yield a solid. The material waspurified by reverse phase HPLC. LC/MS m/z 267.1 (MH+), R_(t) 1.57minutes.

Example 164-Amino-5-(1H-benzimidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one

[0259] LiHMDS (4.3 eq) was added to ethyl 1H-benzimidazol-2-ylacetate(1.1 eq) and 2-aminothiophene-3-carbonitrile (1.0 eq) in THF at 0° C.After 1 hour, the resulting mixture was warmed to room temperature andthen stirred overnight. The mixture was quenched with an aqueoussaturated NH₄Cl solution and extracted with EtOAc. The organic layer waswashed with H₂O and brine, dried over Na₂SO₄, filtered, and concentratedin vacuo to yield a brown solid. LC/MS m/z 283.1 (MH+), R_(t) 1.88minutes.

Example 177-Amino-6-(1H-benzimidazol-2-yl)-3,4-dihydro-5H-imidazo[4,5-b]pyridin-5-one

[0260] LiHMDS (4.4 eq) was added to ethyl 1H-benzimidazol-2-ylacetate(1.0 eq) and 5-amino-1H-imidazole-4-carbonitrile (1.0 eq) in THF at 0°C. After 1 hour, the resulting mixture was warmed to room temperatureand then stirred overnight. The mixture was quenched with an aqueoussaturated NH₄Cl solution and extracted with EtOAc. The organic layer waswashed with H₂O and brine, dried over Na₂SO₄, filtered, and concentratedin vacuo to yield a brown solid. LC/MS m/z 267.1 (MH+), R_(t) 1.47minutes.

Example 184-Amino-5-(1H-benzimidazol-2-yl)-1-methyl-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0261] 5-Amino-1-methyl-1H-pyrazole-4-carbonitrile (1.0 eq) and ethyl1H-benzimidazol-2-ylacetate (1.0 eq) were dissolved in THF and driedover sieves. LiHMDS (3 eq) was added dropwise and the mixture stirredfor 18 hours. The mixture was filtered and diluted with EtOAc, thenwashed with an aqueous saturated NH₄Cl solution. The aqueous layer waswashed with EtOAc (3×), and the organic layers combined, dried overMgSO₄, and concentrated yielding pure product. LC/MS m/z 281.0 (MH+),R_(t) 1.41 minutes.

Assay Procedures In vitro Kinase Assays for Receptor Tyrosine Kinases

[0262] The kinase activity of various protein tyrosine kinases can bemeasured by providing ATP and a suitable peptide or proteintyrosine-containing substrate, and assaying the transfer of phosphatemoiety to the tyrosine residue. Recombinant proteins corresponding tothe cytoplasmic domains of the flt-1 (VEGFR1), KDR (VEGFR2), and bFGFreceptors were expressed in Sf9 insect cells using a Baculovirusexpression system (InVitrogen) and purified via Glu antibody interaction(for Glu-epitope tagged constructs) or by Metal Ion Chromatography (forHis₆ tagged constructs). For each assay, test compounds were seriallydiluted in DMSO then mixed with an appropriate kinase reaction bufferplus ATP. Kinase protein and an appropriate biotinylated peptidesubstrate were added to give a final volume of 100 μL, reactions wereincubated for 1-2 hours at room temperature and stopped by the additionof 50 μL of 45 mM EDTA, 50 mM Hepes pH 7.5. Stopped reaction mix (75 μL)was transferred to a streptavidin coated microtiter plate (BoehringerMannheim) and incubated for 1 hour. Phosphorylated peptide product wasmeasured with the DELFIA time-resolved fluorescence system (Wallac),using a Eu-labeled anti-phosphotyrosine antibody PT66 with themodification that the DELFIA assay buffer was supplemented with 1 mMMgCl₂ for the antibody dilution. Time resolved fluorescence was read ona Wallac 1232 DELFIA fluorometer. The concentration of each compound for50% inhibition (IC₅₀) was calculated by non-linear regression using XLFit data analysis software.

[0263] Flt-1, KDR, and bFGFR kinases were assayed in 50 mM Hepes pH 7.0,2 mM MgCl₂, 10 mM MnC1 ₂, 1 mM NaF, 1 mM DTT, 1 mg/ml BSA, 2 μM ATP, and0.42 μM biotin-GGGGQDGKDYIVLPI-NH₂. Flt-1, KDR, and bFGFR kinases wereadded at 0.1 μg/mL, 0.05 μg/mL, or 0.1 μg/mL respectively.

[0264] Each of the following compounds was synthesized and assayed usingthe procedures described above:

[0265]4-(1-azabicyclo[2.2.2]oct-3-ylamino)-3-(1H-benzimidazol-2-yl)-6-fluoro-1,7-naphthyridin-2(1H)-one;

[0266]4-(1-azabicyclo[2.2.2]oct-3-ylamino)-3-(1H-benzimidazol-2-yl)-6-chloro-1,7-naphthyridin-2(1H)-one;

[0267] 3-benzimidazol-2-yl-4-hydroxyhydropyridino[3,4-b]pyridin-2-one;

[0268]4-hydroxy-3-(5-methylbenzimidazol-2-yl)hydropyridino[3,4-b]pyridin-2-one;

[0269] 4-amino-3-benzimidazol-2-ylhydropyridino[3,4-b]pyridin-2-one;

[0270] 4-amino-3-(5-methylbenzimidazol-2-yl)hydropyridino[3,4-b]pyridin-2-one;

[0271]4-amino-3-[5-(2-morpholin-4-ylethoxy)benzimidazol-2-yl]hydropyridino[3,4-b]pyridin-2-one;

[0272][2-(4-amino-2-oxohydropyridino[3,4-b]pyridin-3-yl)benzimidazol-5-yl]-N,N-dimethylcarboxamide;

[0273]4-amino-3-(5-morpholin-4-ylbenzimidazol-2-yl)hydropyridino[3,4-b]pyridin-2-one;

[0274]4-amino-3-{5-[3-(dimethylamino)pyrrolidinyl]benzimidazol-2-yl}hydropyridino[3,4-b]pyridin-2-one;

[0275]4-amino-3-(3H-imidazo[4,5-b]pyridin-2-yl)-1,7-naphthyridin-2(1H)-one;

[0276]4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1,7-naphthyridin-2(1H)-one;

[0277]4-amino-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-1,6-naphthyridin-2(1H)-one;

[0278]4-amino-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-1H-benzimidazol-2-yl}-1,5-naphthyridin-2(1H)-one;

[0279]4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1,5-naphthyridin-2(1H)-one;

[0280] 3-(1H-benzimidazol-2-yl)-4-hydroxy-1,8-naphthyridin-2(1H)-one;

[0281]4-amino-5-(1H-benzimidazol-2-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one;

[0282] 4-amino-5-(1H-benzimidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one;

[0283]7-amino-6-(1H-benzimidazol-2-yl)-3,4-dihydro-5H-imidazo[4,5-b]pyridin-5-one;and

[0284]4-amino-5-(1H-benzimidazol-2-yl)-1-methyl-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one.

[0285] Each of the above compounds displayed an IC₅₀ value of less than10 μM with respect to VEGFR1, KDR, and bFGF.

[0286] It should be understood that the organic compounds according tothe invention may exhibit the phenomenon of tautomerism. As the chemicalstructures within this specification can only represent one of thepossible tautomeric forms, it should be understood that the inventionencompasses any tautomeric form of the drawn structure.

[0287] It is understood that the invention is not limited to theembodiments set forth herein for illustration, but embraces all suchforms thereof as come within the scope of the following claims.

What is claimed is:
 1. A compound having the structure I, a tautomer ofthe compound, a pharmaceutically acceptable salt of the compound, or apharmaceutically acceptable salt of the tautomer

wherein, Y is selected from the group consisting of —OH, —OR⁸ groups,—SH, —SR⁹ groups, —NR¹⁰R¹¹ groups, —CN, —C(═O)—R¹² groups, substitutedand unsubstituted alkyl groups, substituted and unsubstituted alkenylgroups, substituted and unsubstituted alkynyl groups, substituted andunsubstituted aralkyl groups, substituted and unsubstitutedheterocyclylalkyl groups, substituted and unsubstituted alkylaminoalkylgroups, substituted and unsubstituted dialkylaminoalkyl groups,substituted and unsubstituted arylaminoalkyl groups, substituted andunsubstituted diarylaminoalkyl groups, substituted and unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted and unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted and unsubstitutedheterocyclyl groups, substituted and unsubstituted aryl groups,substituted and unsubstituted hydroxyalkyl groups, substituted andunsubstituted alkoxyalkyl groups, substituted and unsubstitutedaryloxyalkyl groups, and substituted and unsubstitutedheterocyclyloxyalkyl groups; Z is selected from the group consisting ofO, S, and NR¹³ groups; R¹ and R² join to form a 5 to 7 memberedsubstituted or unsubstituted ring comprising at least one O, N, or Satom; R³ and R¹³ may be the same or different and are selected from thegroup consisting of H, —OH, substituted and unsubstituted alkoxy groups,substituted and unsubstituted aryloxy groups, —NH₂, substituted andunsubstituted alkylamino groups, substituted and unsubstituted arylaminogroups, substituted and unsubstituted dialkylamino groups, substitutedand unsubstituted diarylamino groups, substituted and unsubstituted(alkyl)(aryl)amino groups, substituted and unsubstitutedheterocyclylamino groups, substituted and unsubstituteddiheterocyclylamino groups, substituted and unsubstituted(alkyl)(heterocyclyl)amino groups, substituted and unsubstituted(aryl)(heterocyclyl)amino groups, substituted and unsubstitutedheterocylyloxy groups, substituted and unsubstituted alkyl groups,substituted and unsubstituted aryl groups, —C(═O)H, —C(═O)-alkyl groups,and —C(═O)-aryl groups; R⁴, R⁵, R⁶, and R⁷ may be the same or differentand are independently selected from the group consisting of H, Cl, Br,F, I, —NO₂, —CN, —OH, —OR¹⁴ groups, —NR¹⁵R¹⁶ groups, —C(═O)R¹⁷ groups,—SH, —SR¹⁸ groups, —S(═O)R¹⁹ groups, S(═O)₂R²⁰ groups, substituted andunsubstituted amidinyl groups, substituted and unsubstituted guanidinylgroups, substituted and unsubstituted primary, secondary, and tertiaryalkyl groups, substituted and unsubstituted aryl groups, substituted andunsubstituted alkenyl groups, substituted and unsubstituted alkynylgroups, substituted and unsubstituted heterocyclyl groups, substitutedand unsubstituted alkylaminoalkyl groups, substituted and unsubstituteddialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkylgroups, substituted and unsubstituted diarylaminoalkyl groups,substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted and unsubstituted heterocyclylalkyl groups, substituted andunsubstituted aminoalkyl groups, substituted and unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted and unsubstitutedhydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups,substituted and unsubstituted aryloxyalkyl groups, and substituted andunsubstituted heterocyclyloxyalkyl groups; R⁸ is selected from the groupconsisting of substituted and unsubstituted alkyl groups, substitutedand unsubstituted aryl groups, substituted and unsubstitutedheterocyclyl groups, substituted and unsubstituted heterocyclylalkylgroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups,—N(alkyl)₂ groups, —N(alkyl)(aryl) groups, —N(aryl)₂ groups,—C(═O)NH(heterocyclyl) groups, —C(═O)N(heterocyclyl)₂ groups,—C(═O)N(alkyl)(heterocyclyl) groups, and —C(═O)N(aryl)(heterocyclyl)groups; R⁹ and R¹⁸ may be the same or different and are independentlyselected from the group consisting of substituted and unsubstitutedalkyl groups, and substituted and unsubstituted aryl groups; R¹⁰ isselected from the group consisting of H, substituted and unsubstitutedalkyl groups, substituted and unsubstituted aryl groups, and substitutedand unsubstituted heterocyclyl groups; R¹¹ is selected from the groupconsisting of H, substituted and unsubstituted alkyl groups, substitutedand unsubstituted aryl groups, substituted and unsubstitutedheterocyclyl groups, —OH, alkoxy groups, aryloxy groups, —NH₂,substituted and unsubstituted heterocyclylalkyl groups, substituted andunsubstituted aminoalkyl groups, substituted and unsubstitutedalkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkylgroups, substituted and unsubstituted arylaminoalkyl groups, substitutedand unsubstituted diarylaminoalkyl groups, substituted and unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted alkylaminogroups, substituted and unsubstituted arylamino groups, substituted andunsubstituted dialkylamino groups, substituted and unsubstituteddiarylamino groups, substituted and unsubstituted (alkyl)(aryl)aminogroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted(aryl)(heterocyclyl)aminoalkyl groups, substituted and unsubstitutedhydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups,substituted and unsubstituted aryloxyalkyl groups, and substituted andunsubstituted heterocyclyloxyalkyl groups; R¹² is selected from thegroup consisting of H, —OH, alkoxy groups, aryloxy groups, —NH₂,—NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂groups, —N(alkyl)(aryl) groups, substituted and unsubstituted alkylgroups, substituted and unsubstituted aryl groups, —NH(heterocyclyl)groups, —N(heterocyclyl)₂ groups, —N(alkyl)(heterocyclyl) groups, and—N(aryl)(heterocyclyl) groups; R¹⁴ is selected from the group consistingof substituted and unsubstituted alkyl groups, substituted andunsubstituted aryl groups, substituted and unsubstituted heterocyclylgroups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)H,—C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)-heterocyclyl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups,—C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl)groups, —C(═O)NH-heterocyclyl groups, —C(═O)N-(heterocyclyl)₂ groups,—C(═O)N(alkyl)(heterocyclyl) groups, —C(═O)N(aryl)(heterocyclyl) groups,substituted and unsubstituted aminoalkyl groups, substituted andunsubstituted alkylaminoalkyl groups, substituted and unsubstituteddialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkylgroups, substituted and unsubstituted diarylaminoalkyl groups,substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted and unsubstituted heterocyclylaminoalkyl groups, substitutedand unsubstituted diheterocyclylaminoalkyl groups, substituted andunsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted andunsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted andunsubstituted alkoxyalkyl groups, substituted and unsubstitutedaryloxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups,and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹⁵ isselected from the group consisting of H, substituted and unsubstitutedalkyl groups, substituted and unsubstituted aryl groups, and substitutedand unsubstituted heterocyclyl groups; R¹⁶ is selected from the groupconsisting of H, substituted and unsubstituted alkyl groups, substitutedand unsubstituted aryl groups, substituted and unsubstitutedheterocyclyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups,—C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl)groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted andunsubstituted aminoalkyl groups, substituted and unsubstitutedalkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkylgroups, substituted and unsubstituted arylaminoalkyl groups, substitutedand unsubstituted diarylaminoalkyl groups, substituted and unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted and unsubstitutedheterocyclylalkyl groups, —C(═O)-heterocyclyl groups,—C(═O)-O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)-N(heterocyclyl)₂ groups, —C(═O)-N(alkyl)(heterocyclyl) groups,—C(═O)-N(aryl)(heterocyclyl) groups, substituted and unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted and unsubstitutedhydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups,substituted and unsubstituted aryloxyalkyl groups, and substituted andunsubstituted heterocyclyloxyalkyl groups; and R¹⁷, R¹⁹, and R²⁰ may bethe same or different and are independently selected from the groupconsisting of H, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl)groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups,—N(heterocyclyl)₂ groups, substituted and unsubstituted alkyl groups,substituted and unsubstituted aryl groups, —OH, substituted andunsubstituted alkoxy groups, substituted and unsubstituted heterocyclylgroups, substituted and unsubstituted aryloxy groups, heterocyclyloxygroups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkylgroups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, and—N(aryl)O-aryl groups.
 2. The compound according to claim 1, wherein Yis selected from the group consisting of —OH, —OR⁸ groups, and —NR¹⁰R¹¹groups.
 3. The compound according to claim 1, wherein Y is a —NR¹⁰R¹¹group.
 4. The compound according to claim 1, wherein Z is an NR¹³ group.5. The compound according claim 1, wherein R⁴ and R⁷ are hydrogen and R⁵and R⁶ are selected from the group consisting of hydrogen and alkylgroups having from 1 to 4 carbon atoms.
 6. The compound according toclaim 1, wherein R⁵ or R⁶ is an OR¹⁴ group and R¹⁴ is an alkyl, aryl,heterocyclyl, or heterocyclylalkyl group.
 7. The compound according toclaim 1, wherein R⁵ or R⁶ is a —OCH₂(CH₂)_(q)(heterocyclyl) group and qis 0, 1, 2, 3, or
 4. 8. The compound according to claim 1, wherein R¹⁷is selected from the group consisting of substituted and unsubstitutedalkyl groups, substituted and unsubstituted aryl groups, —NH₂,—NH(alkyl) groups, —N(alkyl)₂ groups, —NH(aryl) groups, —N(aryl)₂groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl) groups,—N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups,—N(heterocyclyl)₂ groups, and N-containing heterocycles, wherein theN-containing heterocycles are bonded to the carbonyl carbon of the—C(═O)—R¹⁷ group through either a nitrogen atom or a carbon atom in therings of the N-containing heterocycles.
 9. A compound having thestructure III, a tautomer of the compound, a pharmaceutically acceptablesalt of the compound, or a pharmaceutically acceptable salt of thetautomer

wherein, W¹, W², W³, and W⁴ are selected from C or N, and at least oneof W¹, W², W³, or W⁴ is N; X¹, X², X³, and X⁴ are selected from C or N,and at least one of X¹, X², X³, or X⁴ is N; Y is selected from the groupconsisting of H, —OH, —OR¹⁰ groups, —SH, —SR¹¹ groups, —NR¹²R¹³ groups,—CN, —C(═O)—R¹⁴ groups, substituted and unsubstituted alkyl groups,substituted and unsubstituted alkenyl groups, substituted andunsubstituted alkynyl groups, substituted and unsubstituted aralkylgroups, substituted and unsubstituted heterocyclylalkyl groups,substituted and unsubstituted alkylaminoalkyl groups, substituted andunsubstituted dialkylaminoalkyl groups, substituted and unsubstitutedarylaminoalkyl groups, substituted and unsubstituted diarylaminoalkylgroups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted and unsubstituted heterocyclylaminoalkyl groups, substitutedand unsubstituted diheterocyclylaminoalkyl groups, substituted andunsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted andunsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted andunsubstituted heterocyclyl groups, substituted and unsubstituted arylgroups, substituted and unsubstituted hydroxyalkyl groups, substitutedand unsubstituted alkoxyalkyl groups, substituted and unsubstitutedaryloxyalkyl groups, and substituted and unsubstitutedheterocyclyloxyalkyl groups; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R¹ may bethe same or different and are independently selected from the groupconsisting of H, Cl, Br, F, I, —NO₂, —CN, —OH, —OR¹⁵ groups, —NR¹⁶R¹⁷groups, —C(═O)R¹⁸ groups, —SH, —SR¹⁹ groups, —S(═O)R²⁰ groups, S(═O)₂R²¹groups, substituted and unsubstituted amidinyl groups, substituted andunsubstituted guanidinyl groups, substituted and unsubstituted primary,secondary, and tertiary alkyl groups, substituted and unsubstituted arylgroups, substituted and unsubstituted alkenyl groups, substituted andunsubstituted alkynyl groups, substituted and unsubstituted heterocyclylgroups, substituted and unsubstituted alkylaminoalkyl groups,substituted and unsubstituted dialkylaminoalkyl groups, substituted andunsubstituted arylaminoalkyl groups, substituted and unsubstituteddiarylaminoalkyl groups, substituted and unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted and unsubstitutedheterocyclylalkyl groups, substituted and unsubstituted aminoalkylgroups, substituted and unsubstituted heterocyclylaminoalkyl groups,substituted and unsubstituted diheterocyclylaminoalkyl groups,substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups,substituted and unsubstituted (aryl)(heterocyclyl)aminoalkyl groups,substituted and unsubstituted hydroxyalkyl groups, substituted andunsubstituted alkoxyalkyl groups, substituted and unsubstitutedaryloxyalkyl groups, and substituted and unsubstitutedheterocyclyloxyalkyl groups, and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ maybe absent; R¹ is absent or H if W¹ is N; R² is absent or H if W² is N;R³ is absent or H if W³ is N; R⁴ is absent or H if W⁴ is N; R⁵ is absentor H if X¹ is N; R⁶ is absent or H if X² is N; R⁷ is absent or H if X²is N; R⁷ is absent or H if X³ is N; R⁹ is selected from the groupconsisting of H, —OH, substituted and unsubstituted alkoxy groups,substituted and unsubstituted aryloxy groups, —NH₂, substituted andunsubstituted alkylamino groups, substituted and unsubstituted arylaminogroups, substituted and unsubstituted dialkylamino groups, substitutedand unsubstituted diarylamino groups, substituted and unsubstituted(alkyl)(aryl)amino groups, substituted and unsubstituted alkyl groups,substituted and unsubstituted aryl groups, —C(═O)H, —C(═O)-alkyl groups,and —C(═O)-aryl groups; R¹⁰ is selected from the group consisting ofsubstituted and unsubstituted alkyl groups, substituted andunsubstituted aryl groups, substituted and unsubstituted heterocyclylgroups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)H,—C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkyl groups,—C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl)groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups,—C(═O)N(alkyl)(aryl) groups, —NH₂, —NH(alkyl) groups, —NH(aryl) groups,—N(alkyl)₂ groups, —N(alkyl)(aryl) groups, —N(aryl)₂ groups,—C(═O)NH(heterocyclyl) groups, —C(═O)N(heterocyclyl)₂ groups,—C(═O)N(alkyl)(heterocyclyl) groups, and —C(═O)N(aryl)(heterocyclyl)groups; R¹¹ and R¹⁹ may be the same or different and are independentlyselected from the group consisting of substituted and unsubstitutedalkyl groups, and substituted and unsubstituted aryl groups; R¹² isselected from the group consisting of H, substituted and unsubstitutedalkyl groups, substituted and unsubstituted aryl groups, and substitutedand unsubstituted heterocyclyl groups; R¹³ is selected from the groupconsisting of H, substituted and unsubstituted alkyl groups, substitutedand unsubstituted aryl groups, substituted and unsubstitutedheterocyclyl groups, —OH, alkoxy groups, aryloxy groups, —NH₂,substituted and unsubstituted heterocyclylalkyl groups, substituted andunsubstituted aminoalkyl groups, substituted and unsubstitutedalkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkylgroups, substituted and unsubstituted arylaminoalkyl groups, substitutedand unsubstituted diarylaminoalkyl groups, substituted and unsubstituted(alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted alkylaminogroups, substituted and unsubstituted arylamino groups, substituted andunsubstituted dialkylamino groups, substituted and unsubstituteddiarylamino groups, substituted and unsubstituted (alkyl)(aryl)aminogroups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkylgroups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,—C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups—C(═O)N(alkyl)(aryl) groups, —C(═O )-heterocyclyl groups,—C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstitutedhydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups,substituted and unsubstituted aryloxyalkyl groups, and substituted andunsubstituted heterocyclyloxyalkyl groups; R¹⁴ is selected from thegroup consisting of H, —OH, alkoxy groups, aryloxy groups, —NH₂,—NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂groups, —N(alkyl)(aryl) groups, substituted and unsubstituted alkylgroups, substituted and unsubstituted aryl groups, —NH(heterocyclyl)groups, —N(heterocyclyl)₂ groups, —N(alkyl)(heterocyclyl) groups, and—N(aryl)(heterocyclyl) groups; R¹⁵ is selected from the group consistingof substituted and unsubstituted alkyl groups, substituted andunsubstituted aryl groups, substituted and unsubstituted heterocyclylgroups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)H,—C(═O)-alkyl groups, —C(═O)-aryl groups, —(C═O)-heterocyclyl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups,—C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl)groups, —C(═O)NH-heterocyclyl groups, —C(═O)N-(heterocyclyl)₂ groups,—C(═O)N(alkyl)(heterocyclyl) groups, —C(═O)N(aryl)(heterocyclyl) groups,substituted and unsubstituted aminoalkyl groups, substituted andunsubstituted alkylaminoalkyl groups, substituted and unsubstituteddialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkylgroups, substituted and unsubstituted diarylaminoalkyl groups,substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups,substituted and unsubstituted heterocyclylaminoalkyl groups, substitutedand unsubstituted diheterocyclylaminoalkyl groups, substituted andunsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted andunsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted andunsubstituted alkoxyalkyl groups, substituted and unsubstitutedaryloxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups,and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹⁶ isselected from the group consisting of H, substituted and unsubstitutedalkyl groups, substituted and unsubstituted aryl groups, and substitutedand unsubstituted heterocyclyl groups; R¹⁷ is selected from the groupconsisting of H, substituted and unsubstituted alkyl groups, substitutedand unsubstituted aryl groups, substituted and unsubstitutedheterocyclyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups,—C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups,—C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl)groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted andunsubstituted aminoalkyl groups, substituted and unsubstitutedalkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkylgroups, substituted and unsubstituted arylaminoalkyl groups, substitutedand unsubstituted diarylaminoalkyl groups, substituted and unsubstituted(aryl)(alkyl)aminoalkyl groups, substituted and unsubstitutedheterocyclylalkyl groups, —C(═O)-heterocyclyl groups,—C(═O)-O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,—C(═O)-N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups,—C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstitutedheterocyclylaminoalkyl groups, substituted and unsubstituteddiheterocyclylaminoalkyl groups, substituted and unsubstituted(heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted(heterocyclyl)(aryl)aminoalkyl groups, substituted and unsubstitutedhydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups,substituted and unsubstituted aryloxyalkyl groups, and substituted andunsubstituted heterocyclyloxyalkyl groups; and R¹⁸, R²⁰, and R²¹ may bethe same or different and are independently selected from the groupconsisting of H, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl)groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups,—N(heterocyclyl)₂ groups, substituted and unsubstituted alkyl groups,substituted and unsubstituted aryl groups, —OH, substituted andunsubstituted alkoxy groups, substituted and unsubstituted heterocyclylgroups, substituted and unsubstituted aryloxy groups, heterocyclyloxygroups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkylgroups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, and—N(aryl)O-aryl groups.
 10. The compound according to claim 9, whereinone of W¹, W², W³, and W⁴ is N.
 11. The compound according to claim 9,wherein one of X¹, X². X³, and X⁴ is N.
 12. The compound according toclaim 9, wherein Y is selected from the group consisting of H, —OH,—OR¹⁰ groups, and —NR¹²R¹³ groups.
 13. The compound according to claim9, wherein Y is a —NR¹²R¹³ group.
 14. The compound according to claim 9,wherein R⁵ is H, X⁴ is N, and R⁶ and R⁷ are selected from the groupconsisting of H and alkyl groups having from one to four carbon atoms.15. The compound according to claim 9, wherein R⁶ or R⁷ is an —OR¹⁵group and R¹⁵ is an alkyl, aryl, heterocyclyl, or heterocyclylalkylgroup.
 16. The compound according to claim 9, wherein R⁶ or R⁷ is a—OCH₂(CH₂)_(q)(heterocyclyl) group and q is 0, 1, 2, 3, or
 4. 17. Thecompound according to claim 9, wherein R¹⁸ is selected from the groupconsisting of substituted and unsubstituted alkyl groups, substitutedand unsubstituted aryl groups, —NH₂, —NH(alkyl) groups, —N(alkyl)₂groups, —NH(aryl) groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups,—NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups,—N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, andN-containing heterocycles , wherein the N-containing heterocycles arebonded to the carbonyl carbon of the —C(═O)—R¹⁸ group through either anitrogen atom or a carbon atom in the rings of the N-containingheterocycles.
 18. A pharmaceutical formulation, comprising the compoundaccording to claim 1 in combination with a pharmaceutically acceptablecarrier.
 19. A method of treating a patient in need of an inhibitor ofvascular endothelial growth factor receptor tyrosine kinase, comprisingadministering an effective amount of the pharmaceutical formulationaccording to claim 18 to a patient in need thereof.
 20. A pharmaceuticalformulation, comprising the compound according to claim 9 in combinationwith a pharmaceutically acceptable carrier.
 21. A method of treating apatient in need of an inhibitor of vascular endothelial growth factorreceptor tyrosine kinase, comprising administering an effective amountof the pharmaceutical formulation according to claim 20 to a patient inneed thereof.